CN108405002A - Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples - Google Patents
Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples Download PDFInfo
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- CN108405002A CN108405002A CN201810120041.2A CN201810120041A CN108405002A CN 108405002 A CN108405002 A CN 108405002A CN 201810120041 A CN201810120041 A CN 201810120041A CN 108405002 A CN108405002 A CN 108405002A
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- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
- C12Q1/6806—Preparing nucleic acids for analysis, e.g. for polymerase chain reaction [PCR] assay
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- B01L3/502715—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures by integrated microfluidic structures, i.e. dimensions of channels and chambers are such that surface tension forces are important, e.g. lab-on-a-chip characterised by interfacing components, e.g. fluidic, electrical, optical or mechanical interfaces
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Abstract
Techniques described herein is usually related to from multiple samples especially from the system of extraction from biological material polynucleotides, and is additionally related to the system for then expanding and detecting extracted polynucleotides.More specifically, the technology is related to microfluidics systems, and the microfluidics systems carry out PCR in microfluidic channels on the multiple nucleotide samples of purpose, and detect those nucleotide.
Description
The application is (the international Shen of Chinese invention patent application 200880106760.3 for the applying date being on July 14th, 2008
Please number PCT/US2008/008640) divisional application again of (division Chinese invention patent application 201310455953.2 for the first time).
Prioity claim
This application requires the priority power of the U.S. Provisional Patent Application serial number 60/959,437 proposed on July 13rd, 2007
The benefit of priority for the S. Utility application serial 11/985,577 that benefit and on November 14th, 2007 propose, by the two
By reference to being fully incorporated in this.
Technical field
Techniques described herein is usually related to
System, and it is additionally related to the system for then expanding and detecting extracted polynucleotides.More specifically, the technology is related to micro-
Fluid system is seen, the microfluidics systems carry out PCR in microfluidic channels on the multiple nucleotide samples of purpose, and
Detect those nucleotide.
Background technology
Medical diagnosis industry is the key factor on health care today basis.However currently, regardless of route, examine in vitro
It is disconnected to analyze the bottleneck for having become patient care.In this regard, there are several reasons.First, many diagnostic analysis only use height profession
Equipment carry out, be expensive and can only be operated by trained clinician.This equipment finds only in some positions-
Often only one in any given urban area.This means that most of hospitals need sample being sent to these places and be used for
Analysis, therefore freight and transport delay are generated, and be possibly even sample loss or mishandling.Second, it is begged for
The equipment of opinion is not generally obtainable when needed, is run with batch, therefore for many sample delay processing times,
Because they have to wait for machine to be full of before they can run.
It understands sample flow and resolves into several committed steps, it is desirable to consider the side of automation as much as possible
Formula.For example, once being extracted from patient, biological sample must be suitable for relating generally to place using the form of the processing scheme of PCR,
To expand purpose carrier (such as nucleotide).Once amplification, the presence of the purpose nucleotide from sample is it will be clear that ground determines.
It prepares and is currently the step of spending time taking and labour intensive for the sample of PCR, although nobody needs special skills, and
It can be usefully automation.By comparison, the step of such as PCR and nucleotide detect (or " nucleic acid test "), only leads to
Often in the personal range for the special training for touching special equipment.
In the presence of the needs for such method and apparatus, the method and device carry out sample in parallel on sample
Prepared by product, with and without PCR and detection on the biological sample of preparation, and preferably have high throughput, but with can be with
In the mode that care location routinely carries out, sample need not be passed out to special equipment.
The discussion of background technology herein is included to explain the range of invention as described herein.This is not recognized
To be to recognize that any material of reference is delivered in the priority date of claim any one, it is known that, or usually
Common sense part.
In the whole explanations and claim of specification, wording " including (comprise) " and its variation, such as " including
(comprising) " and " including (comprises) " is not intended to exclude other additives, ingredient, integer or step.
It summarizes
A kind of diagnostic device, the diagnostic device include:It is configured to extract the of nucleic acid containing nucleic acid samples from multiple simultaneously
One component, wherein the first component includes:One or more holders are respectively configured to receive the sample of certain amount and corresponding
The fixator of number, wherein each fixator includes process chamber, waste chamber, one or more pipette tips and one or more
A storage, wherein one or more of storages respectively containing sufficient amount for carrying out from one kind of sample extraction nucleic acid or more
Kind reagent;It is configured to the magnetic separator moved relative to the process chamber of each fixator;Independent heating is configured at each
Manage the heater assembly of room;It is distributed with the liquid for being configured to be carried out at the same time fluid transmission operation on two or more fixators
Device;Be configured to expand the second component of the nucleic acid from the multiple sample extraction simultaneously, wherein the second component includes:One
A or multiple compartments are respectively configured to receive microfluid box, wherein the box is configured to individually receive and individually expand
From the nucleic acid of multiple sample extractions;With one or more detecting systems.
A kind of diagnostic device, the diagnostic device include:One or more holders are placed in each of the holder
The sample containing nucleic acid of certain amount and the fixator of respective number, wherein each fixator includes process chamber, waste chamber, one
A or multiple pipette tips, and one or more storage, wherein one or more of storages use containing sufficient amount respectively
In carrying out from one or more reagents of sample extraction nucleic acid;Close to the processing of each of one or more of fixators
The magnetic separator that the second position can be moved to from first position of room;Heater group including certain amount unit heater
Each one with the process chamber of part, the unit heater thermally contacts;One or more compartments, each compartment have
It is complementary to the shape of microfluid box shaped, wherein the box includes the entrance of certain amount, each of the entrance is with one
A fluid communication for determining number of channels expands the nucleic acid from an extraction of the sample of the number in the channel, and
And the wherein described box further includes the one or more windows for the nucleic acid for allowing detection to expand;Liquid with one or more dispensing heads
Body distributor, wherein the liquid distributor can be moved to from the first position on the first fixator on the second fixator
The second position, and can be moved on first fixator not from the first position on first fixator
Same position, and on one of the entrance that the quantity can also be moved to from the position on one of the fixator
Position;With the one or more detecting systems positioned close to one or more of windows.
A kind of diagnostic instrments, the diagnostic instrments include:From the liquid handling of the sample extraction nucleic acid in composite reagent item
Unit;The microfluid box being connect with heating element, carries out real-time PCR on the nucleic acid from the sample extraction;With to make
User provide diagnose the sample whether the detector containing purposeful nucleotide.
The method using the diagnostic device is also described herein, the method includes using described device is parallel to diagnose one
The method of fixed number mesh sample.
A kind of composite reagent fixator, the composite reagent fixator include:Connect following item:Single treatment pipe;One
A or multiple storages, each self-sustaining are selected from consisting of the following group of reagent:Sample preparation reagents, for the first analyte
PCR reagent and one or more liquid reagents;Waste pipe;It is configured to keep one or more of one or more pipette tips
A jack;Be configured to the pipette tip set around one or more of pipette tips.
A kind of liquid distributor, the liquid distributor include:One or more sensors;Manifold;With it is described branched
One or more pumps of fluid communication;With one or more dispensing heads of the branched fluid communication;D translation is provided
The rack of freedom of motion;With the electrical connection for being externally controlled device and receiving electric signal, wherein the liquid distributor except through
One or more of pumps are not used for entrance or the outlet of fluid.
A kind of separator for magnetic-particle, the separator include:Be in line one or more magnets of adjustment;Machine
Dynamic axis, thereon one or more magnets can increase or decline in this way so that one or more of magnets are real
Now close proximity to the storage containing magnetic-particle;With the control circuit for controlling the motor-driven axis movement.
A kind of integrated purification device and heater comprising:Heater assembly, wherein the heater assembly includes multiple only
Controllable unit heater is found, receiving and heat treatment chamber are respectively configured to;Be in line one or more magnets of adjustment;
Motor-driven axis, on it one or more magnets can rise or fall in such a way, the mode is one
Or multiple magnets are realized close proximity to one or more process chambers;It is moved and the heating with the motor-driven axis is controlled
The control circuit of device unit heating.
A kind of preparation facilities, the preparation facilities include:First component is configured to containing from certain amount simultaneously
The sample extraction nucleic acid of nucleic acid, wherein the first component includes:One or more holders are each configured to receive the number
Sample and respective number fixator, wherein each fixator includes process chamber, waste chamber, one or more pipettes are inhaled
Head, and one or more storage, wherein one or more of storages respectively one or more reagents containing sufficient amount, are used
In carrying out from sample extraction nucleic acid;It is configured to the magnetic separator moved relative to the process chamber of each fixator;It is configured to solely
The heater assembly of each of the vertical heating process chamber;Be configured to be carried out at the same time fluid on two or more fixators
Transmit the liquid distributor of operation;Be configured to receive and store the second component of the nucleic acid of the sample extraction from the number.
A kind of preparation facilities, the preparation facilities include:One or more holders above place one in each of described holder
Fixator of the fixed number purpose containing nucleic acid samples and respective number, wherein each fixator includes process chamber, waste chamber, one or more
A pipette tip, and one or more storages, wherein one or more of storages are used to carry out containing sufficient amount respectively
From one or more reagents of sample extraction nucleic acid;Process chamber close to each fixator can be moved to from first position
The magnetic separator of two positions;Include the heater assembly of certain amount unit heater, each of described unit heater with
Process chamber contacts;The liquid distribution of the second position on the second fixator can be moved to from the first position on the first fixator
Device;With the holding compartment with certain amount compartment, wherein each compartment stores the core that is extracted from one of sample of the number
Acid.
A kind of composite reagent fixator, the composite reagent fixator include:A kind of, the item is connected to:Single place
Reason pipe;One or more storages, each storage are kept selected from consisting of the following group of reagent:Sample preparation reagents, and it is a kind of
Or plurality of liquid reagent;Waste pipe;It is configured to keep one or more jacks of one or more pipette tips;Be configured to
Around the pipette tip set of one or more of pipette tips.
This technology is also comprised for the method from multiple sample parallel extraction nucleic acid, and the method uses described herein
Device.
The summary of the figure of selection
Figure 1A shows the schematic diagram of preparation facilities;Figure 1B shows the schematic diagram of diagnostic device.
The schematic diagram of Fig. 2 display control circuits.
Fig. 3 A and 3B show the external view of exemplary device.
The exemplary interior views of Fig. 4 display devices.
Fig. 5 shows the perspective view of exemplary sample fixer holder.
Fig. 6 shows perspective view of the holder together with unit heater of Fig. 5.
Fig. 7 shows the perspective view of exemplary sample fixer holder.
Fig. 8 A-8K show a variety of views of the holder of Fig. 7.
Fig. 9 shows the device region for the holder for being configured to receive Fig. 7.
Figure 10 A and 10B show the first exemplary embodiment of the reagent fixator with liquid relief pipe sleeve, with perspective view
The form of (Figure 10 A) and underside view (Figure 10 B).
Figure 11 is displayed without the exemplary embodiment of the reagent fixator of liquid relief pipe sleeve, with perspective view.
Figure 12 A-12C show the second exemplary embodiment of the reagent fixator with liquid relief pipe sleeve, with perspective view (figure
12A) and the form of viewgraph of cross-section (Figure 12 B) and sectional view (Figure 12 C).
Star feature on Figure 13 A and 13B visualizingre agent pipes inside, with cross section (Figure 13 A) and vertical view (Figure 13 B)
Form.
Figure 14 shows pipetting sequence together with the Reagent Tube with star feature.
The embodiment that Figure 15 shows laminate layers.
Figure 16 shows the pipetting sequence together with laminate layers.
Figure 17 A-17D show the exemplary kit containing fixator and reagent.
Figure 18 shows liquid distributor.
Figure 19 A-19C show liquid distributor.
Figure 20 shows exemplary distribution manifold.
Figure 21 shows the scanning read head for being connected to liquid distributor.
Figure 22 shows bar code scanner with viewgraph of cross-section.
Figure 23 shows the bar code reader being located in above microfluid box.
Figure 24 shows pipette tip sensor.
Figure 25 A and 25B show the exemplary device for removing pipette tip.
Figure 26 shows the unit heater of perspective view and viewgraph of cross-section form.
The integrated heater and separator unit of Figure 27 show cross section plane views.
The automatic loader of Figure 28 display boxes.
Figure 29 display box stackers.
Figure 30 shows the box stacker in place that box is transmitted to automatic loader.
Figure 31 display box Load Systems.
Figure 32 shows the processing unit of used box.
Figure 33 shows full and empty structural form box stacker.
Figure 34 shows microfluid box, read head and box pallet.
Figure 35 shows the cross section of pipetting head and box in place in microfluidic device.
Figure 36 shows the exemplary microfluid box with 3-tier architecture.
Figure 37 shows the plan view of microfluid circuit and entrance in exemplary multichannel box.
Figure 38 A show exemplary multichannel box.
Figure 38 B show a part for exemplary multichannel box.
Figure 39 A, 39B show the exemplary Microfluidic networks in the channel of multichannel box;
Figure 40 A-40C show the figure of exemplary microfluid valve.Figure 40 A also show the valve of open state, and close
The valve of state.
Figure 41 shows discharge orifice.
Figure 42 shows exemplary height multiplexing microfluid box;
Figure 43-46 shows many aspects of exemplary height multiplexing microfluid box;With
Figure 47 A-C show many aspects of the height multiplexing microfluid box of radial configuration.
Figure 48 shows the view of microfluid box cross-sectional form.
Figure 49 A, 49B show PCR reative cells and associated heater.
The thermal image of heater circuit in Figure 50 display operations.
Figure 51 A-51C show a variety of incision sections that can be during PCR thermal cycles for improving cooling rate.
Figure 52 is shown in the figure of temperature during PCR method to the time, is carried out on microfluid box as described in this article.
Figure 53 shows the assembly method of box described further herein.
Figure 54 A and 54B show the exemplary device for carrying out wax deposit.
Figure 55 A and 55B are shown in exemplary wax droplet deposition to microfluid valve.
Figure 56 shows the covering of exemplary multichannel microfluid box upper heater element arrays, many of microfluid
Network is visible.
Figure 57 shows the viewgraph of cross-section of exemplary detector.
Figure 58 shows the perspective view of detector in read head.
Figure 59 shows the sectional view of exemplary detector in read head.
Figure 60 shows the external view of the exemplary multiplexing read head of detector array wherein.
Figure 61 shows the cross section view of the exemplary multiplexing read head of detector array wherein.
Figure 62 shows the block diagram for the exemplary electronic circuit being connect with detector described herein.
Figure 63 shows exemplary fluid dispensing system.
Figure 64 shows exemplary heater/separator.
Figure 65 A and 65B show the exemplary feature based on computer user interface.
Figure 66 schematically shows the element design of preparation facilities.
Figure 67 shows the element design of exemplary preparation facilities.
Figure 68 shows the schematic design of the element of diagnostic device.
Figure 67 shows the element design of exemplary diagnostic device.
The exemplary diagnostic device of the displays of Figure 70 and 71 is outwardly and inwardly.
Figure 72 A and 72B show the thermal cycle unit for being configured to receive microfluid box.
Figure 73 schematically shows the element design of high efficiency diagnostic device.
Figure 74 shows the element design of exemplary high efficiency diagnostic device.
Figure 75 shows the plan view of the channels 24- microfluid box.
Figure 76 shows the perspective view of the box of Figure 75.
Figure 77 shows the sectional view of the box of Figure 75.
Figure 78 shows exemplary detection unit.
Figure 79 A, 79B show the cross sectional portion of the detection unit of Figure 78.
The adjustment of detection unit of the displays of Figure 80 and 81 with microfluid box.
Figure 82 and 83 respectively shows outside and the section of optical component.
Figure 84 schematically shows Scorpion reactions.
Head of pipette during Figure 85 A-85C are illustrated schematically in a variety of preparation process uses.
Figure 86-91 shows the exemplary design of electronic control circuit, and wherein Figure 86 is electronic block diagram, and Figure 87 is processor
Base board block diagram, Figure 88 are MUX plate block diagrams, and Figure 89 is MUX plate block diagrams, and Figure 90 is micro-heater plate block diagram, Figure 91
It is motor control panel block diagram.
It is described in detail
It includes DNA (DNA) and RNA (ribonucleic acid) tests that nucleic acid as used herein, which tests (NAT) to be,
General terms.To be that specific exemplary regulation is described in this for RNA and for DNA.It should be appreciated that being wherein not specific to
The generalization explanation of RNA or DNA is equally applicable to respectively, or can be easily adapted to appointing for herein described minor change
What one, such as submit to those of ordinary skill in the art.It will also be understood that term nucleic acid and polynucleotides can be herein can be mutual
It uses with changing.
Consequently found that device described herein is applied to analyze any sample containing nucleic acid used in any purposes,
Including but not limited to it is used for heredity test and the clinical trial of multiple infectious disease in the mankind.Clinical assays presently, there are, and
The target that device and method herein can be used to test can be bacterium or virus, and include, but are not limited to:Trachoma clothing
Substance (Chlamydia Trachomatis) (CT);Neisseria gonorrhoeae (Neisseria Gonorrhea) (GC);Streptococcus
Group B;HSV;HSV classifying types;CMV;Influenza A and B;MRSA;RSV;TB;Trichomonas (Trichomonas);Adenovirus;It is rich
Moral spy Bordetella (Bordatella);BK;JC;HHV6;EBV;Enterovirus;With Mycoplasma pneumoniae (M.pneumoniae).
Device herein can be configured to run on experimental bench or in similar environment, and when in regular working day
About 45 sample/hours can be tested when whole day continuous operation.The number can according to the test number provided in single batch and
Increase, such as will be apparent from described herein.Result from independent primary sample is available generally in less than 1 hour
's.
In the case of used herein, term " component " should be used to indicate component element, and each element can be with
With individual, clear and/or independent function, but it is configured to run together one or more required to generate
As a result.It is unwanted to be, each element in component be directly connected to or with each other element direct communications.Moreover,
Connectivity in Various Components can be realized under the aided case of the element such as processor of the member exterior.
Device is summarized
Be further described in this device with Various Components and can be configured at least two forms, preparation and diagnosis
, as shown respectively in Figure 1A and 1B.The preparation facilities 981 for carrying out sample preparation being described further herein shows
Meaning property summarizes display in figure 1A.The general introduction of diagnostic device 971 is shown in fig. ib.The geometry of the element of system 971,981 is pacified
Row's display is in figure 1A and Figure 1B is exemplary and is not intended to be restrictive.
Processor 980, such as microprocessor, are configured to control the multiple element function of shown system, and therefore with need
Each of to be controlled such element communication.It should be appreciated that many such control functions arbitrarily can be carried out manually, and
Not under processor control.Moreover, hereinafter, when described device operates, described in multiple functions sequence it is unlimited
It is formed on the sequence that wherein processor executes instruction.Thus, processor 980 can be configured to receive the number about sample to be analysed
According to, for example, come from sample reader 990, can be bar code reader, optical character recognition reader or RFID scanner (are penetrated
Frequency label reader).It will also be understood that although single-processor 980 is shown as all operationss of control device 971 and 981,
It is such operation can easily be distributed on more than one processor.
Processor 980 can be configured to receive user's instruction from input 984, wherein such instruction may include
Start the instruction of analysis sample, and the instruction of selection operating condition.Although not showing in figs. 1 a and 1b, in a variety of implementations
In scheme, input 984 may include selected from consisting of the following group of one or more input units:Keyboard, touch-sensitive surface,
Microphone, tracking plate, retina scanners, the line holographic projections and mouse of input unit.Suitable input unit can be further
Reader including formatting electronic media, such as, but is not limited to, flash card, memory stick, USB- sticks, CD or floppy disk.Input
Device may further include security feature such as finger-printer reader, retina scanners, magnetic stripe reader or barcode reading
Device is done so for determining that system user is in fact authorized to according to the identification feature of the preloaded of authorized user.Input
Device can be in addition and at the same time work as recording with output device of the sample analysis in relation to data.For example, if
Input unit be format electronic media reader, then it is also possible that medium logger.It can be in this way one
The data that such medium is recorded in kind of device include but are not limited to, and analyze related environmental information, such as temperature or
Humidity and diagnostic result, and identify the data of sample of interest.
Processor 980 can also be configured to connect with display 982, so as to for example, by being transmitted to about the information of analysis
Display and therefore it is passed to system user.Such information includes but is not limited to:The current state of device;PCR
The process of thermal cycle;With the warning message under system or box performance unfavorable condition.In addition, processor 980 can transmit one
Or multiple problems promote user to provide and react it input to be shown on display 982.Thus, in certain embodiment party
In case, input 984 and display 982 are mutually integrated.
Processor 980 can be transferred to output device such as printer, visual display with arbitrary disposition at by analysis result
Device, using the display or loud speaker of line holographic projections, or combinations thereof.
Processor 980 further arbitrarily can be connected to computer network via communication interface such as network interface
988.Communication interface can be selected from consisting of the following group of one or more interfaces:It is connected in series with, is connected in parallel, wireless network
Network connects, and USB connections are connected with cable network.Therefore, long-range to use when the system compatibly determines address on network
Person can access processor and transmit instruction, input data, or retrieval data, can such as be stored in and connect with the processor
In the memory (not shown) connect, or on some other computer-readable media with processor communication.Therefore described to connect
Mouth can also allow data extracting remote location, such as PC, and personal digital assistant or network storage device are such as
Computer server or disk farm.Described device may be configured to allow user by analysis result direct generation of electricity
Mail is to all other parties, such as healthcare provider or diagnostic device or patient.
In addition, in multiple embodiments, described device can also include being configured to from processor, input unit, and lead to
The one or more of letter interface receives the data storage medium of data, and the data storage medium is to be selected from consisting of the following group
One or more media:Hard disk drive, CD drive, flash card and CD-Rom.
Processor 980 can be further configured to a variety of aspects of control sample preparation and diagnosis, as follows in general introduction, and
And as further described in detail herein.In figs. 1 a and 1b, device 981 (or 971) is configured to together with complementary holder 970
Operation.As described further herein, described holder itself be configured to receive certain amount be suitable for post-processing (work up) and
The biological sample 996 of the form of diagnostic analysis and the fixator 972 of certain amount, the fixator 972 are equipped with plurality of reagents,
Pipette tip and storage.The holder is configured so that, during sample post-processes, by sample in respective fixator
Processing, the processing includes independently being heated and being cooled down via heater assembly 977.The heating function of heater assembly can
To be controlled by processor 980.Heater assembly 977 is operated together with such as magnetic separator of separator 978, can also be by
The control of processor 980 is to move into and leave close proximity to the one or more processing being connect with the fixator 972
Room, wherein there are particle such as magnetic-particles.
The liquid distributor 976 that can be similarly controlled by processor 980 is configured to the respective sample in fixator 972
A variety of absorptions and batch operation are carried out on product, fluid and reagent, to realize from sample extraction nucleic acid.Liquid distributor 976 can be with
Such operation is carried out at the same time in multiple fixators.Sample reader 990 is configured to will be about sample and in some cases
Fixator identification flag transmission to processor 980.In some embodiments, sample reader is connected to liquid distribution
Device and the label that can therefore read the sample disposed thereon about liquid distributor.In other embodiments, sample is read
Read device be not connected to the liquid distributor and be it is independently moveable, under processor control.Liquid distributor 976
It is configured to using the fluid aliquot containing the nucleic acid from one or more sample extractions, and directs them into storage area
974, can be cooler.For example, the PCR pipe corresponding to each sample is contained in region 974.In other embodiments, no
There are individual region 974, but to can be configured to cooling one or more fixators 972 former so as to the nucleic acid of extraction for cooler
Position is cooling and stores, rather than is transmitted to separated position.
Figure 1B shows the illustrative embodiments of diagnostic device 971, and the diagnostic device 971 has and the device of Figure 1A
981 identical elements still instead of storage area 974, have wherein receive box 994 to receive compartment 992.Receive compartment with
Heater 998 is connected, and the heater 998 itself can in such a way be controlled by processor 980, and the mode is,
Specific time during analysis heats the specific region of the box.Thus liquid distributor 976 is configured to take and be contained from one
The fluid aliquot of the nucleic acid of a or multiple sample extractions and the respective entrance for directing them into box 994.Box 994 configures
At such as by carrying out the respective nucleic acid of PCR amplification.Processor is also arranged to control detector 999, is examined from the receiving of box 994
Severed finger shows.The diagnosis can be for transmission to output device 986 and/or display 982, as described above.
It can design respectively according to design principle known in the art and semiconductor processing method and manufacture suitable place
Manage device 980.
The device embodiment shown in sketch map in Figure 1A and 1B, such as other exemplary embodiment party described herein
Case is the same, is advantageous, because they do not need to locate in the same in the device compatibly configured to store reagent.The system
Embodiment, or other exemplary embodiments herein, be all not required to will be configured to from such as external storage container such as bottle,
Tank or reservoir receive the entrance or outlet port of reagent.Therefore, the device in Figure 1A and 1B is self-contained and together with fixation
Device 972 is run together, wherein the fixator reagent is pre-packaged, the position for being exclusively used in reagent storage such as within it.
The device of Figure 1A and 1B can be configured to be operated in single position, such as laboratory position, or can be just
Take formula so that they can be adjoint, for example, doctor, or other health care professionals, can go out in different places
Examine patient.Described device is typically equipped with power cord so that they can be from mainly for answering or generator receives AC power supplies.Optionally
Transformer (not shown) be configured in each device or outside is located between supply hub and system, by AC input power
It is transformed into DC outputs, for being used by described device.Described device can also be configured to transport by using one or more battery
Row therefore also usually equipped with batter-charghing system, and alerts if the power of battery becomes too low a variety of polices of user
Device is accused, reliably to start or complete diagnostic analysis.
In other embodiments, the device of Figure 1A and 1B can further be configured to the sample analysis of multiplexing
And/or more batches of sample analysis, wherein for example, single holder keeps single batch of sample.In such construction, the example of system,
As summarized in Figure 1B, receives and handle multiple microfluid boxes 994.Therefore, each element conduct shown in Figure 1A and 1B
The manyfold of sample batch exists, although multiple element can be only fitted in common shell.
In another construction, system configuration is at receiving and handle multiple boxes, but one or more of Figure 1A and 1B
Element is general for multiple boxes.For example, single device can be configured with multiple compartments for receiving box, but general procedure
Device, detector and user interface are compatibly configured to allow while parallel, continuous or control multiple boxes simultaneously.Further may
, such a embodiment also utilize simple sample reader and single output device.
In another construction, system configuration shown in Figure 1B is at single box is received, wherein the single box is configured to
Parallelly and it is processed independently of each other 1 or more, for example, 2,3,4,5 or 6 samples.Multiple samples can be handled for generating
The exemplary technology of the box of product describes elsewhere, for example, in US application serial No. 60/859,284, by reference to combining
In this.
Further consistent with the prior art, box can be labeled, for example, sample is indicated with molecular barcode, to promote
The risk minimization for being tracked into sample, and sample being made to mix.Method for marking in this way describes elsewhere, for example,
In U.S. Patent Application Publication No. 10/360,854, it is incorporated herein by reference.
Control electronics 840 is implemented as device 971 or 981, is illustrated schematically in the block diagram in Fig. 2, can be in a variety of realities
The scheme of applying includes one or more functions, for example, it is used for main control 900, multiplexing 902, display control 904, detection
Device control 906, etc..Main control function can be used as controlling the hub of electronic device 840 in the device of Figure 1A and 1B, and
The communication and control of a variety of electric functions can be managed.Main control function can also be supported such as to beat with user or output device
The electricity of print machine 920 and communication interface 908 and optional diagnosis and security functions.Together with main control function 900, multichannel
Adjuster function 902 can control sensing data 914 and output current 916 to help to control heater assembly 977.Display
Control function 904 can control output, if applicatory, for translating the input from touch screen LCD 846, therefore at certain
Graphical interface can be supplied to user by its in a little embodiments.Detector functions 906 can be in controlling electronic device 840
It realizes, carrys out self-detector 999 such as one using typical control and processing circuit to collect, digitize, filter, and/or transmit
The data of a or multiple fluorescence detectors.The other function being not shown in Fig. 2 includes but not limited to be used for control figure 1A and 1B
The control function of middle element such as liquid distributor, separator, cooler, and receive the data from sample reader.
In being shown in figures 3 a and 3b according to the exemplary device of Figure 1A or the function of 1B.Exemplary dress in Fig. 3 A and 3B
It sets and is shown in shell 985 and covering 987 in the closed position of Fig. 3 A and in the open position of Fig. 3 B, to disclose
Internal feature 995.Covering 987 optionally has handle 989, is shown as elliptical and rises from blanket surface, but its
Can be other shapes such as square, rectangle or it is round and its can be recessed in it is in blanket surface or flush.
Covering 987 is shown as with hinge, however other constructions such as sliding covering is also possible.Buffer 991 is for preventing
Only covering keeps covering 987 to stablize the point in open position from falling too far and/or offer backward.Shell 985 is in addition
It is shown as that there are one or more communication port 983, and one or more power ports 993, can be positioned at other places,
Such as on the back side of instrument.
The device of Figure 1A and 1B can optionally include one or more foot stabilizations, so that the main body of described device is increased and be
On the surface that system 100 is configured, therefore allow the ventilation under system 100, and improved raising system is also provided for user
The ability of system 100.There may be 2,3,4,5 or 6 or with last foot, the size of system 100 is depended on.Such foot preferably by
Rubber, plastics or metal are made, and in some embodiments, can rise 10 main body of system on the surface that it is located at
High about 2 arrive about 10mm.
Fig. 4 shows the exemplary construction of the part inside exemplary device, such as shows in figures 3 a and 3b.In Fig. 4
Middle display holder 970, the reagent fixator 972 containing certain amount and Patient Sample A 996, and, close proximity to it, have
Have box 994 receives compartment 992, for carrying out PCR on the polynucleotides from sample extraction.
Holder
Described device further comprises being configured to can be plugged into can remove in described device and from described device one
A or multiple holders, each holder is further configured to receive multiple reagent fixators, and receives multiple sample cells, wherein institute
It states reagent fixator and sample cell to correspond, and the wherein described reagent fixator respectively contains enough reagents so as to from sample
It extracts polynucleotides and polynucleotides is positioned to PCR- and use form.It is further described through elsewhere herein exemplary
Reagent fixator.
Device may include 1,2,3,4 or 6 holder, and each holder can receive 2,4,6,8,10,12,16, or
20 samples each at least have one or more pipettes such as in sample cell 802 and the fixator of respective number 804
Suction nozzle, and one or more reagent containers.
Holder is generically configured to receive the reagent fixator 804 of certain amount, it is all those of as further described herein, institute
Support configuration is stated at fixator as one or more is kept, is allowed on the platform of laboratory using being stored in the fixator
Reagent, or be located in the reserved area of described device, the fixator allowed to can be used for the one or more of described device
Other functions, such as automatic liquid relief, the Magnetic Isolation of the heating of processing tube and affine pearl.
Two perspective views of exemplary holder 800 are configured to receive 12 sample cells in 12 channels and 12 corresponding
Reagent fixator, display in Figure 5.If this paper is used herein above and below holder, channel is designed to receive sample cell and phase
The holder reserved area for the reagent fixator answered.Two perspective views of identical exemplary holder are shown in together with unit heater
In Fig. 6.
Multiple views of second exemplary holder 800 are also arranged to receive 12 sample cells and 12 reagent fixators, show
Show in Fig. 7 and Fig. 8 A-8K.Thus, following view is shown:Side plan view (Fig. 8 A);Front plan views, display sample cell (figure
8B);Back plan view, visualizingre agent fixator (Fig. 8 C);Rearview, visualizingre agent fixator (Fig. 8 D);Front view shows sample
It manages (Fig. 8 E);Top, the insertion (Fig. 8 F and 8G) of visualizingre agent fixator;Top shows the slot for being inserted into reagent fixator
(Fig. 8 H);The record (Fig. 8 I) of top view visualizingre agent fixator;The closing of holder be partial insertion state/from device remove
(Fig. 8 J);With the holder kept by handle, (Fig. 8 K) removed from device.As described further herein, for receiving Fig. 7
Exemplary movable supporting frame diagnosis or the recessed area in preparation facilities, display in fig.9.For receive shape, appearance,
With form difference rather than the recessed area of other suitable configurations of the different other holders of function is consistent with description herein.
Two exemplary holders being shown in figure are non-limiting, and two exemplary holders is used to be used as explanation now
The holder of property, describes the general features of holder contemplated herein.For example, the embodiment is shown herein, at least first
Channel and second channel are mutually parallel, a kind of construction increasing liquid relief efficiency.Usually, neighbouring when being mutually parallel
Sample channel at their respective midpoint to separating 24mm.(other distances are possible, such as separately 18mm, or separate 27mm.
The distance between described midpoint depends on the pitch-row of jet pipe in liquid distributor, as further described herein.Spacing is protected
The multiple held in 9mm can be easily loaded into 96 orifice plates (wherein usually, the spaced apart 9mm in hole) from holder.Usually,
Equally, the holder is such, so that multiple reagent fixators in multiple channels are maintained at identical height relative to each other.
The support configuration is that reagent fixator is reversible at reagent fixator, the mode is received in such a way
Ground snap-on is locked in position, and when reagent accesses it and holder from a place be transported to another ground
When just or being inserted into device or removing from described device, keep stablizing.In each embodiment, the second position it is every
One includes being configured to the single-orientated mechanical keys for receiving reagent fixator.In Figure 5, it is shown that, reagent fixator water
Flat to slide into the slot of vertical orientation, each fixator one is located in the holder.In such a embodiment, Gu
It is engaged with complemental groove in slot top at the edge for determining the connecting element on device.In Fig. 8 F, 8G and 8I, it is shown that, reagent is solid
Determine device to engage with holder via mechanical keys, it is stable and in place that the mechanical keys are kept fixed device.For example, mechanical
Key may include rising or reagent fixator is allowed in recessed part when being engaged with the complementary portion of reagent fixator
In snap-on to the second position.The embodiment shown in can further be seen that reagent fixator has first end and second end,
And mechanical keys include the fisrt feature for being configured to engage with first end, and are configured to that with reagent fixator mistake cannot be inserted into
The second feature that mode around route is engaged with second end.
In certain embodiments, reagent fixator respectively locks position in the bracket, such as with cam lock mechanism,
It locks with being regarded as audio and/or physically, or such as uses mechanical keys.The holder can be configured in this way so as to when positioning
When among it, using liquid distributor described further herein, fixator is directed at pipette tip sensor appropriate
(pick up).Moreover, the second position in each channel can accommodate one or more pipette tips deeply enough, such as wrap
It is contained in pipette tip set.
In certain embodiments, support configuration is respectively adjacent to corresponding at the sample received in independent sample cell 802
Fixator 804 install, such as in the side of holder 800.Sample cell can lead to sample identification check device such as bar code and read
Device is read, as described further herein.In Figure 5, sample cell is maintained to its bottom by cylindric receiving element.Scheming
In 7, it is shown that, sample cell may remain in its top and bottom, such as by being configured to receive the recessed of sample bottom of the tube
Into part 803, and it is configured to keep the hole 805 on sample cell top.The hole can be in ring or the ring or sheet metal of opening
Hole.Recess can be such as Fig. 7, and wherein it is the angled piece of metal shell, with sufficiently large hole to accommodate sample
Pipe.
Holder can be designed in this way, so as to it is easily removed from device and is transported to other than separating device
Laboratory environment, such as platform and described device, for example, allowing that sample cell and reagent fixator are easily loaded into holder
In.In certain embodiments, support Design and is not easy to topple over during transportation at stablizing on a horizontal surface, and
And for this purpose, the holder has one or more (such as 2,3,4,6,8) foot 809.In certain embodiments,
The holder has handle 806 to be easy to lift and move, and as shown in Figure 5, handle can be locked into upright position
In, during transportation, the same risk for reducing holder and being dumped.Handle optionally can have soft folder 808 in its centre.
In the embodiment of Fig. 7, Carrying handles surround the axis shifted from the axis by the holder center of gravity and position when loaded, and
Freely drop to the position concordant with the rack upper surface under its dead weight.
The embodiment of Fig. 5 has metal bottom element 810, has 4 foots 811, when the holder is inserted into dress
When the private part set, the foot 811 also serves as position locator.Connect the handle to base member.Receive sample and fixation
The part of the holder 812 of device can be made of plastics, and include 12 slots, and can be disposable.
In the embodiment of Fig. 7, the holder includes:Shell;Multiple channels in the shell, and it is wherein described
Each channel in multiple channels includes:It is configured to receive the first position of sample cell;Be configured to receive the of reagent fixator
Two positions;With the recording element for receiving compartment for being complementary to diagnostic device.Usually, the shell is made of metal such as aluminium,
It can be light, but can also be machined to high tolerance (high tolerance), and be it is sufficiently solid with protect
Card holder keeps stablizing when in diagnostic device.Recording element in Fig. 7 includes a exacting tolerances bolt (tight in four (4)
Tolerance peg) 815, each holder angle positions one.Such bolt is such, so that they are close to and closely
It is cooperated in the complimentary aperture for receiving compartment of described device and therefore stablizes the holder.For example, having 2 or 3, or it is more than 4
Other embodiments of a such bolt meet embodiment herein.
In particular, the shell in the embodiment of Fig. 7 includes horizontal cell 821, and be connected to two of horizontal cell or
Multiple perpendicular elements 822, and be such, so that the second position in each respective channel is the recess within horizontal cell
Point.Two or more perpendicular elements 809 in the embodiment of Fig. 7 are configured to allow holder stick-up on it.It is described outer
Shell may further include two or more foots or bearing, be symmetrically attached to the first and second perpendicular elements and work as be located in
Give the holder other stability when bench top.
Moreover, in the embodiment of Fig. 7, shell further comprises multiple spacer elements 825, and each configuration is a pair of adjacent
Between close channel.Optionally, such spacer element can be with arranged perpendicular between the channel.
Although not shown, holder may further include to be accorded with each channel attached gap marker.It is logical
Road identifier can be permanent or interim label such as unique number or letter, or can be RFID or bar code, or can
It is unique coloured label to be for special modality.
By support configuration at the appropriate location that can be easily placed at so as to it in this way in instrument, and give user
Positive feedback, such as audio or physically, it is correct placement.In certain embodiments, the holder can be locked out
Into position.It is desirable that holder is properly positioned, and is impermissible for moving behind, so as to liquid distributor
Movement will not be destroyed during liquid operates.The holder is therefore with recording element to ensure to be properly positioned.In the reality of Fig. 7
It applies in scheme, the recording element includes two or more positioning pins, is configured to ensure that the holder can only be taken with single
To being placed in the diagnostic device;And stability is provided for the holder when being placed in the diagnostic device.Fig. 7's
Embodiment optionally has sensor and actor 817, is configured to the correct placement of holder in indication diagnosis device.Such one
Kind sensor can be communicated with processor 980 to provide warning for user, the warning such as heard, or is passed via interface
The visual alert passed, if the holder is not correct in place.If it can also be configured to detect error in place
Then prevent sample preparation procedure from starting or continuing.
In certain embodiments, the internal stent around the processing tube position in a variety of fixators is configured to have and use
The gap of the heater assembly and/or magnetic separator that are further described in this article.For example, the support configuration is at this
Sample is received so as to the process chamber of independent fixator by the unit heater in heater assembly described further herein.
When previous sample holder is prepared by device, there is moveable holder can enable the user to keep
Next holder sample is loaded and is in line, to make device usage time maximize.
It, can also be easily in instrument in the case where any sample overflows it or is only used as laboratory article General Maintenance
Outer cleaning support.
In certain embodiments, the holder has one or more disposable parts.
Fixator
Figure 10 A and 10B show the view of exemplary fixator 501 described further herein.Figure 11 shows another
The plan view of exemplary fixator 502, as further described herein.Figure 12 A show the exemplary fixation of perspective view
Device 503, and the identical fixator of Figure 12 B show cross section plane views.Figure 12 C show fixation identical with Figure 12 A and 12B
The sectional view of device.All these exemplary fixators will now be described, and the others consistent with written explanation herein are fixed
Device, although not being shown as specific embodiment.
The exemplary fixator shown in Figure 10 A, 10B, 11,12A, 12B and 12C can individually referred to as " combination it is primary
Property item ", or " combobar ", because being intended to use them as single unit, the single unit is configured to remain execution sample
Whole reagents and storage necessary to preparing, and because they are arranged in the form of item.Consistent with description herein
It is, although it is contemplated that other geometry arrangement of multiple storages, so that the explanation is not limited to straight line or strip arrangement, but
It may include round or grid arrangement to be.
Some reagents included in the fixator are provided as liquid, and others can be provided as solid.
In some embodiments, different types of container or pipe are for storing the liquid from those of store solids container or pipe.
The fixator can be disposable, such as designed for single application, then abandon it.
Fixator is generally made of plastics such as polypropylene.The plastics be it is such, so as to it have some it is flexible with
Promotion is placed into holder, as further described herein.However, plastics are generally rigid, so that fixator will not be
It significantly sagging or bending and is not easy to deform during routine operation and transport under its dead weight, and because without allowing to try
Agent is leaked out from it.
Fixator includes connecting element 510, as follows with one or more features.Connecting element 510 will be for that will fix
The multiple element of device links together.Connecting element 510 have upside 512 and, the downside 514 relative to the upside.
In Figure 10 B, the view of display downside 514, with connect at connecting element edge with multiple jacks, processing tube and Reagent Tube
Multiple pillars 597.Pillar 597 is optional, and can completely or partially be omitted, or can be by making fixator be held together
Other part portions or all replace.
The fixator is configured to:Fixed to connecting element and with the hole 522 being located in the connecting element
Processing tube 520;At least one jack 530 is located in the connecting element, and the prong configuration is at the disposable liquid relief of receiving
Pipe suction nozzle 580;Two or more Reagent Tubes 540 in the downside of connecting element are configured, each Reagent Tube, which has, is located at connection member
Ingate 542 in part;With one or more storages 550, it is located in connecting element, wherein one or more of storages are respectively
It is configured to the complementary receptacle such as Reagent Tube (not shown) for receiving to be inserted into from the upside of connecting element 512.
Fixator is usually such, so that the connecting element, processing tube and two or more Reagent Tubes are by single portion
Part is made, such as polyacrylic component.
Fixator is also usually such, so that at least described processing tube and described two or multiple Reagent Tubes are translucent
's.
One or more storages 550 are configured to receive Reagent Tube, Reagent Tube one kind containing sufficient amount or more respectively
Kind is typically solid-state, the reagent of such as lyophilized form, for carrying out from the sample extraction nucleic acid being connected with fixator.Storage can
To be entirely identical size and shape, or can be mutually different size and shape.Storage 550 is shown as with open bottom
Portion, but it is not limited to such form, and can be closed, the entrance 552 being different from 510 upside of connecting element.It is preferred that
Ground, storage 550 is configured to receive the container usually used in lab analysis field, or compatibly configuration supplies fixator herein
Container used.The container be usually with fixator separately store to promote sample operation because solid reagent usually needs
To be different from the condition of storage of liquid reagent.In particular, many solid reagents can be with the normal moisture-sensitive of right and wrong.
Snap on system (snapped-in) Reagent Tube containing different reagents can be different color or color coding,
For easily being differentiated by user.For example, they can be made of the material of different colours, such as coloured plastics, or can be with
There are some species of identification label, such as colored stripes or point on them.They, which can also have, is printed on side
Label, and/or can be on the top sealant on have identifier such as bar code.
Can alternatively the integration section of fixator and can be and waste chamber by container 554 that storage 550 receives
And/or the container of Reagent Tube same type, or can be unlike this.
In one embodiment, configuration contains freeze-dried reagent in storage 550 (for example, being shown in Figure 12 A and 12C)
Container 554 be 0.3ml pipe, be further configured to their respective bottom interior surface have mulle (see
Figure 13 A and 13B).This is such, when fluid has been added to freeze-dried reagent (it is dry in initial package), in core
During sour extraction process, pipette tip can bottom out in the tube, and remain to withdraw from the pipe almost complete
Portion's fluid, as shown in figure 14.The design of mulle further describes other places herein.
Reagent Tube such as contains freeze-dried reagent, can be by metal foil such as foil sealing at their top, without plastics
Backing layer, as further described herein.
Embodiment 501,502 and 503 is shown to be configured with waste chamber 560, has entrance in the upside of connecting element
Hole 562.Waste chamber 560 is optional, also, in its existing embodiment, is configured to receive used liquid reagent.
In other embodiments, wherein it is not present, and used liquid reagent can be passed to the position other than fixator
And it is disposed in the position, such as, for example, including the sample cell for the original sample for analyzing its content.Waste chamber 560
Illustratively comprise the part of the component of other two or multiple Reagent Tubes 540.It should be appreciated that for example, for the sake of easily manufactured,
Carry out such a arrangement;Other positioning of waste chamber are possible, and embodiment as such, wherein waste chamber is adjacent to reagent
Pipe, rather than it is connected to it via the mode different from connecting element.
Fixator be usually it is such, so as to connecting element, processing tube, two or more Reagent Tubes and waste chamber (if
In the presence of) it is made of single part, it is made of such as polyacrylic material.
The display of embodiment 501 and 503 has liquid relief pipe sleeve 570.This is the optional member of fixator described herein.
It can be permanently or removably fixed to connecting element 510, or can form the list for being for example molded as the fixator
A part for one element.For example, the sectional view of fixator 503 is in the upper surface of moveable liquid relief pipe sleeve 570 in Figure 12 C
Upper display handle connection 574, is engaged with recess complementary in the downside 514 of connecting element 510 or hole.Other connection structures
Making is possible.When pipette tip is placed at least one jack, liquid relief pipe sleeve 570 is generically configured to surround at least one
The low portion of a jack and suction nozzle and pipette tip.In some embodiments, at least one jack includes four
A jack.In some embodiments, at least one jack includes two, three, five or six jacks.
Liquid relief pipe sleeve 570 is typically configured to that there is bottom 576 and configuration to have wall portion between bottom and connecting element
Divide 578.In addition and optionally in wall 578 or in bottom 576 liquid relief pipe sleeve 570 can have one or more cut-off parts
572.Such cut-out provides the ventilation of pipette tip and reduces the total amount of material used in fixator manufacture.Embodiment
The 503 liquid relief pipe sleeves with no such cut-out.In embodiment 501, such a cut-out is shown as the set top
In isosceles triangle;The cut-out of one analogous shape can be found in the corresponding position in the opposite side of set, from Figure 10 A
It is dim that view, which is seen,.Other cut-outs can have it is other triangular shaped, it is circular, it is oval, it is square, it is rectangular
Shape or other polygons or irregular shape, and can be several, such as many in number.Liquid relief pipe sleeve 570
Wall 578 can also have sieve mesh or frame-like structure, with trepanning or gap.In the embodiment with liquid relief pipe sleeve
In, the purposes of set is to collect drop from used pipette tip, and therefore prevent across sample pollution, across the sample dirt
The use from a fixator in similar position to another fixator is contaminated, and/or the fixator is located therein
Any supporting support across sample pollution.Then, typically, bottom 576 is solid and bowl-type (concave surface) so as to drop
It is maintained within it.There is no the embodiment such as 502 of liquid relief pipe sleeve that can use, for example, drop disk or drain outlet, are suitble to
Ground is placed under the pipette tip in one or more jacks, is used for identical purposes.In addition to collecting drop, when
Before or after some liquid processing steps, when suction nozzle is picked and/or falls, pipette tip set prevents or inhibits other
The suction nozzle-of reagent fixator is such as adjacent to those of one positioning of purpose in the bracket, as described further herein-from
It contacts with each other.Contact in neighbouring fixator between suction nozzle is not generally by for example, the sample treatment on control fixator is parallel
Automatic dispensing head desired by, but long pipette tip can easily contact the suction nozzle in neighbouring item, and condition is when falling
Under the suction nozzle when angle slightly offset from vertical.
For the fixator of embodiment 501,502 and 503 all with connecting element, the connecting element is to be configured so that
, so as at least one jack, the respective hole and two or more Reagent Tubes of one or more storages and processing tube, entirely
Portion is aligned relative to each other (that is, their midpoint is located in same axis).However, fixator herein is not limited to
The particular configuration of storage, waste chamber, processing tube, jack and Reagent Tube.For example, if a some holes is interlocked simultaneously relative to each other
And position " outside axis " is occupied, fixator can be made shorter.A variety of storages etc. need not also occupy identical relative to each other
Position, as seen in figs. 12 a and 12b, wherein configuration processing tube is about in the center close to fixator, liquid reagent is stored in
In the storage installed on the side of processing tube, and the storage of solid reagent is kept to be mounted on the other side of the processing tube.
Thus, in Figure 10 A, 10B and 11, processing tube is on one end of connecting element, and pipette is sleeved on the other end, inside
In portion position, it is adjacent to waste chamber and two or more Reagent Tubes.Others configuration is possible, and is such as mounted on processing tube
One end of fixator installs processing tube adjacent to pipette tip and pipette tip set (as further illustrated in this paper), and
And waste pipe is installed adjacent to the processing tube.It should be appreciated that the constructive alternative of the multiple portions of fixator only causes form to become
Change, and the other changes that can be contained in described device are internal, is including but not limited to used for liquid distribution head of pipette, adds
The alternative instruction set of hot device assembly and magnetic separator, as described further herein.
Processing tube 520 can also be snap on system pipe, rather than a part for integrated component.Processing tube 520 is typically used in
The a variety of mixing occurred during sample preparation and reaction process.For example, cytolysis can be happened at processing tube 520
In, this can extract nucleic acid.Then processing tube 520 is with advantage situated makes to be related on the whole that liquid is transmitted to processing tube
The position that 520 head of pipette moving operation minimizes.
Reagent Tube 540 is typically configured to keep liquid reagent, and often pipe is a kind of.For example, in embodiment 501,502, and
In 503, shows three Reagent Tubes containing washing buffer, release buffer solution and neutralization buffer respectively, each of which is used
In sample preparation regulation.
Keep the Reagent Tube 540 of liquid or liquid reagent laminate structures 598 can be used to seal.Laminate structures allusion quotation
There is to type heat sealing layer, plastic layer such as polypropylene layer and metal layer such as aluminium foil, wherein heat sealing layer is adjacent to one or more
A Reagent Tube.The other plastic foil used in the laminated material for the storage containing liquid reagent is typically for preventing
Liquid contacts the aluminium.
The embodiment of two laminate structures, their layer structure is different, and display is in fig.15.In two embodiment party
In case, when such where applicable, heat sealing layer 602, such as other such polymer by laquer or with low melting point are made, and are
In bottom, it is adjacent to the top of fixator.Plastic layer 604 typically at the top of the heat sealing layer on, and typically by polypropylene
It is made, with the thickness in 10-50 micron ranges.Metal layer 608 typically at the top of the plastic layer on, and can be with bonding
Oxidant layer 606 is attached to the aluminium foil layer of plastic layer, such as the first embodiment in Figure 15, or can be direct evaporation or splatter to plastics
The metal layer in position on layer.The exemplary thickness of equivalent layer is shown in fig.15, where it is understood that up to 2 times of thickness
Variant it is consistent with technology herein.In particular, in one embodiment, aluminium foil is 0.1-15 microns of thickness, and is polymerize
Nitride layer is 15-25 microns of thickness.In another embodiment, aluminium is 0.1-1 microns of thickness, and polymeric layer is 25-30 microns
It is thick.
The laminated material configured herein make longer-term storage be easier because fixator include sealing freeze-dried reagent and
Be sealed in it is closely adjacent in liquid presence, this is typically to be difficult to realize.
In one embodiment, the top of Reagent Tube has bevelled edge so as to when aluminium foil thermal is attached to top,
Plastic melt is not in tube edges with external expansion.This is favourable, because, if plastic melt reduces the internal diameter of pipe, it
It will cause to influence pipette tip during operation.In other embodiments, raised planar section 599 promotes laminated material
598 application and removing.On on the upside of the connecting element, and around the convex of the ingate and optional waste chamber for leading to Reagent Tube
Surface 599 is played, is the optional feature of fixator.
The mode that wherein liquid is moved out of is such, and the pipette tip to be passed through the foil is torn through, without moving
Sealing is generated around liquid pipe suction nozzle, in Figure 16.Such a sealing during liquid relief around suction nozzle will be unfavorable, because
A certain amount of air stream is desirable for pipetting.In this case, sealing is not generated, because of laminated material knot
Structure causes the foil pierced through to rest in the position at first used when it is pierced.In Figure 16 above five versions illustrate from
The Reagent Tube of laminated material sealing removes reagent, as described further herein.In A, pipette tip is containing reagent 707
On Reagent Tube about center on position.In B, pipette tip is reduced, is usually controllably reduced, into Reagent Tube, and
Foil 598 is pierced through in so carrying out.The sectional view in the region, which is shown, to be connect with pipette tip in the widest portion across Reagent Tube
The laminated material edge of tactile puncture.In C, pipette tip is slightly withdrawn, the suction nozzle is made to be maintained at the main body of reagent 707
It is interior.Sectional view shows that the foil of puncture has been maintained when it is pierced and pipette tip extends downwardly within Reagent Tube
To the construction that it is used when its most deep position.In D, pipette tip absorption reagent 707, when more and more the elderlys undergo
When such test, its height may be changed.In E, pipette tip is removed completely from Reagent Tube.
A variety of pipes and the material of room can be configured to have at least smooth interior surfaces degree and face coat with reduce DNA and its
Its macromolecular is attached to this.The combination of DNA is undesirable, this is because the sensitivity of reduction, this may cause not collect
The subsequent detection and analysis of DNA on fixator surface.
Processing tube can also have low combination surface, and magnetic beads is allowed easily to be slided up and down in inner wall, without viscous
Close it.Moreover, it has hydrophobic surface coating, fluid static friction can be reduced and therefore reduce nucleic acid and other molecules
Combination.
In some embodiments, the fixator includes recording element such as mechanical keys.Typically, such a key is
A part for connecting element 510.Mechanical keys ensure that fixator is received to exist by complementary elements, for example, the supporting support of device or connecing
In by compartment, the pipetting for reagent in fixator is controlled.Mechanical keys are typically the cut-out (cutout) of specific shape,
It matches the corresponding cut-out of receiving device or projection.Thus, embodiment 501 has mechanical keys 592, in connecting element
It include the cut-out of a pair of of rectangular shape on one end.In addition feature shown in this provides connector, when fixator is inserted into branch
When in frame or another device and removing, suitable handle (purchase) can be obtained by the connector user.Implement
Scheme 501 and 502 also has mechanical keys 590 in the other end of connecting element 510.Key 590 is angled cut-out, and being easy will
Fixator is inserted into holder, and when the complementary angled cut-out in the adjacent recessed area for being configured to receive fixator
When, good record is ensured wherein.Certainly, other variants of mechanical keys are consistent with description herein:For example, bending is cut
Disconnected or multiple combinations recesses or projection will all promote the reliable record of fixator.
In some embodiments, it is not shown in Figure 10 A, 10B, 11 or 12A-C, fixator further includes the company of being fixed to
Connect the identifier of element.The identifier can be label, the label that can such as write, bar code, 2 dimension bar codes or RFID
Label.For example, identifier can in order to quickly show what combination reagent be present in fixator, also, thus, it need
What kind of sample preparation regulation.Identifier may also indicate that the batch of fixator manufacture for quality control or keeps note
The purposes of record.Identifier can also allow user by specific fixator and specific sample match.
It should also be as being considered consistent with description herein, in addition fixator can be configured to receive in sample all
Such as in sample cell.Thus, in the embodiment described elsewhere herein, holder receives a fixed number in such a way
The corresponding fixator of purpose sample cell and certain amount, the mode be, sample cell and fixator can dividually and independently
Ground mutually loads.However, in other embodiments, fixator can be configured to also receive sample, such as in sample cell.
And thus, complimentary bracket is configured to receive the fixator of certain amount, wherein each fixator has sample and reagent
And other articles.In such a embodiment, the fixator is configured so that sample can be used for sample identification verifier.
Kit
Fixator described herein can be provided in hermetic bag, to reduce air and moisture and the reagent in fixator
The chance contacted.Such a hermetic bag can contain one or more fixators described herein, and such as 2,4,6,
8,10,12,16,20 or 24 fixators.
Fixator can also be provided for carrying out a part for the kit of sample preparation, wherein the kit packet
Include first bag containing one or more fixators described herein, each fixator be configured with for such as lysis, washing,
With the liquid reagent of release, and with second bag inside inert atmosphere, and contain one or more reagents of freeze-drying PCR reagent
Pipe, as shown in figure 17.Such kit may be configured to provide the analysis of multiple samples, and be tried containing enough PCR
Agent (or other amplifing reagents, such as RT-PCR, transcript mediated amplification, chain, which substitutes, to be expanded, NASBA, what unwindase relied on
Amplification and those of ordinary skill in the art known to it is other and described herein other) to handle such sample and one
The independent fixator of fixed number purpose such as 2,4,6,8,10,12,16,20 or 24 fixators.
Reagent Tube
As referenced elsewhere herein, the container 554 containing freeze-dried reagent is 0.3ml pipes, they
Be additionally configured to have starriness in respective base interior surface or mulle (see Figure 13 A and 13B).With using in this article
Way and for other purposes not described herein others pipes, can be similarly configured.Thus, for example, by star
The benefit that shape pattern provides also appear in containing directly from pipe the Reagent Tube of the fluid sample of liquid relief (and appear in initial
Those of solid pipe, the solid is kept to constitute liquid before liquid relief).It will benefit from other rulers of such starriness pattern
Very little pipe has the size in such as 0.1ml to 0.65ml ranges.
Starriness pattern ensures that, when fluid takes out from the pipe, pipette tip can be down to low spot in the tube,
And it remains to take out all or almost all fluid from the pipe, as shown in figure 14.This is important, because, when with small in this way
Volume work when, and in the presence of target DNA may be with considerably less copy, due to liquid relief it is incomplete caused by sample loss
Each possible degree will be minimized to.
The design of starriness pattern is important, particularly as used for recycling clinical sample in existing for very smallest number
When DNA/RNA.When in the case where pipette is down to bottom of the tube in use, mulle should can pipette most of liquid
(1 microlitre of resid vol <).Surface area and end groove is set to minimize in addition, mulle should be designed so that, the surface
Product and end groove are intended to tool there are two undesirable effect-retention liquid and increase undesirable multinuclear glycosides
The reservation that acid is adsorbed.
Figure 14 will now be described, it is as follows.There is Figure 14 the version of certain amount, A-G respectively to indicate the rank of pipetting in order
Section.In A, the pipette tip 2210 containing liquid 2211 (such as buffer solution) directly or is positioned approximately in Reagent Tube 2200
Center on.The pipe contains the freeze-drying bead 2212 of certain amount, and such as foil of tegillum 2214 seals.The foil can warm
It is sealed on the top of the pipe.Although laminate ply, as described further herein, can be placed on Reagent Tube,
Typically, aluminium foil layer is enough, and middle pipe content is solid, for example, the reagent of freeze-drying.In some embodiments, it tries
The top of agent pipe has the expansion of pipe top edge during heat seal of the bevel edge to reduce the foil in tube top portion.The pipe
Identifiable coding, such as 1-D or 2-D bar codes on top can be also comprised.Such coding can be used to identify storage
Reagent composition wherein, and/or it is used to prepare its lot number mesh and/or term of validity.Coding can use such as inkjet printing
On machine or the printing of transfer printing machine.
Mulle 2203 on 2200 bottom interior surface of display tube.In B, pipette tip is reduced, pierces through sealing 2214,
And it is introduced into the position of 2212 or more particle.In C, liquid 2211 is discharged into from pipette tip on particle, described in dissolving
Particle, as shown in D.After particle is completely dissolved, solution 2218 is formed, pipette tip is reduced to it and mulle
The position of 2203 contacts.In E, cause pipette tip draw solution 2218, and in F, the suction nozzle can be optionally by solution
It is discharged into pipe backward.Freeze-drying ingredient can be promoted to dissolve according to repetition step E and F is required and be mixed into solution.In step
Rapid G withdraws pipette tip from the pipe after drawing and actually entering the solution 2218 of pipette tip as many.
It is desirable that in G, the solution 2218 of 100 volume % is drawn into pipette tip.In other embodiments, and root
According to the attribute of solution 2218, at least solution of 99 volume % is drawn.In other embodiments, at least 98% is drawn, at least
97%, at least 96%, at least 95%, and at least 90% solution by volume.
The design of star or starriness pattern can optimize so that by being moved in the pipette to touch the bottom such as p1000
The flow rate of liquid in the gap between liquid pipe and mulle maximizes, and further describes and proposed on July 13rd, 2007
In U.S. Provisional Patent Application serial number 60/959,437, it is incorporated herein by reference.It should be appreciated that although described herein be related to
The pipette and pipette tip generally used in the sample preparation of biological sample, but the principle and detailed aspect that design are suitable
For other types of pipette and pipette tip, and can so adapt to.
Figure 13 A show the perspective cross-sectional view of the Reagent Tube 2200 with side wall 2201 and bottom 2202.The interior table of bottom
Face 2204 is visible.It is three grooves on top that starriness, which cuts off 2203 local displays,.
Usually, starriness pattern exists as the projection portion in pipe lower inner surface.Thus, manufacture the phase in Reagent Tube
Between, such as by injection molding, the exterior section of mold is the cavity for the outer shape for limiting the pipe.The inside shape of the pipe
Shape is formed by the mold with the exterior section mold concentric locating, and with the starriness structure milled out from its tip.
Thus, when in the space between liquid plastics are injected into two parts of mold, starriness is formed as table in the bottom of the tube
Projection portion on face.
The exemplary mulle 2203 shown with plan view in Figure 13 B is similar to " wheel of ship " and includes center 2209,
Circular rings 2207 placed in the middle and 8 radial components for being configured to radial groove 2205 on center 2209.Each groove is at center
2209 intersect another groove, and have radial extremity, also referred to as vertex (apex) or peak (vertex).Mulle
2203 have 8 grooves, but it is to be understood that the mulle with fewer or greater number groove, such as 3, and 4,6,10, or
12, it will be consistent with design herein.Star-shaped groove number should be the minimum value compatible with effective liquid liquid relief, and also
It is sufficiently spaced apart to not be trapped in any one suction nozzle of the pipette tip used in liquid operation application.
Center 2209 is usually positioned with the bottom geometric center of Reagent Tube 2200 with meeting.The pipe is generally in cross section
On be circular, so identifying that its center (for example, in crosspoint of two diameters) is typically simple.Center 2209 can be with
Such as can be circular chop or projection portion, diametrically more than the friendship by groove 2205 than the bigger shown in Figure 13 B
The region of formation can be put.
Ring 2207 is the optional feature of starriness pattern 2203.Usually, ring 2207 is placed in the middle around center 2209, and
Usually it also has the size corresponding to pipette tip lower surface.Thus, when pipette tip is in 2200 bottom of Reagent Tube
When " touching the bottom ", pipette tip basis rest with ring 2207 to contact.Thus ring 2207 be preferably turned off or it is recessed
Feature, this can accommodate pipette tip and helping and it is guided to be positioned in the bottom center of the pipe.In other embodiment party
In case, there are more than one, such as 2,3 or 4 concentric rings 207.
Mulle is configured to have and obtains fluid from Reagent Tube into the best stream for the pipette tip for being suitble to positioning
The size of speed.Mulle is shown in Figure 13 B, diametrically significantly less than the pipe its widest point diameter.More
In a embodiment, the diameter (being measured from center 2209 to 2205 vertex of groove) of mulle can be the 5- of reagent pipe diameter
20% or reagent pipe diameter 10-25% or the 15-30% of reagent pipe diameter or the 20-40% or reagent of reagent pipe diameter
The 50- of the 25-50% of pipe diameter or the 40-60% or reagent pipe diameter of the 30-50% of reagent pipe diameter or reagent pipe diameter
75% or reagent pipe diameter 65-90%.
Thus groove 2205 separates (occupying the space between adjacent recess) by burr.It is recessed in the embodiment of display
Slot is more narrower (occupying smaller radial angle) than the gap between them.In other embodiments, groove can than them it
Between gap it is proportionally wider.In such embodiments, can be more suitable for they being described as with burr rather than
Groove.In other embodiments, their separated grooves and burr are had in each radial distance of distance center equal
Width.
It can be circular in their lower surface to form the groove of star point, be such as semicircle on cross section
, but usually v-shaped.They can also be trapezoidal on cross section, such as with top more broader than bottom,
It is plane, top is connected with bottom by inclined wall.
In some embodiments, for easy to manufacture, groove terminates on the phase same level of the bottom of the tube.Thus,
Radial extremity all configures on circular circumference.In other embodiments, groove does not terminate on phase same level all.Example
Such as, groove can be terminated alternatively on different level, and thus the end be alternatively arranged at two it is circular corresponding
On circumference, described two circles spatially occupy mutually different plane.
Groove 2205 is shown as (such as measuring to vertex from center 2209) with equal length in Figure 13 B.This need not be as
This.In alternative embodiment, groove can have mutually different length, for example, as the length changed on the groove of change
Degree, wherein there are the grooves of even number.Moreover, vertex can be round, rather than it is outstanding.
Usually, groove is in width and depth uniformly tapering to each corresponding vertex from center 2209.Other structures
It is still possible to make, such as a kind of groove, and constant width or depth are proceeded to specific radial degree by the groove, such as it
Length 30-60%, then narrow or shoal against its vertex.Alternatively, groove can start to narrow at center 2209,
Most wide region is widened into the mid-length close to it, is then narrowed against its vertex.Other possibilities are not this paper institutes
Description, be consistent with mulle.
It it is usually about 50 microns in the width of each groove 2205 of its widest point, and described in 0.3ml pipes
Width usually uniformly attenuates from widest point, closest to or center 2209, culminates.
In 0.3ml pipes, groove is usually about 25-50 microns and depth usually from most deep in the depth of deepest point
Point gradually decreases, and closest to or center 2209, culminates.
In 0.3ml pipes, the starlikeness radius formed by groove is such as measured from center 2209 to the shortest distance on vertex, one
As be about 0.5mm, but can be 0.1-1mm or 0.3-2mm.
In another embodiment, in 0.3ml pipes, groove should be cavetto and be less than 100 microns of depths or small
In 50 microns of depths, or it is less than 25 microns of depths.
Generally there is mulle symmetrical rotary axis, the axis to match perpendicular to the bottom of the tube and by center 2209
It sets, so that groove is symmetrically arranged at around rotary shaft.It means that for n groove, (rotation) axis at center is surrounded
The rotation of 2 π/n can be such that each groove meets with its neighbouring groove.
The star shape shown in Figure 13 B is not limiting, because it includes the recessed of the radial configuration of certain amount
Slot 2205 and optional cyclic rings 2207.The geometry of other star shapes can be used, also, depending on the appearance of manufacture
Yi Xing can be preferred.For example, stars can generate simply by being superimposed two or more polygons, it is described two or
Multiple polygons have common center but are compensated pivotably movable with respect each otherly around the central shaft.(see, such as in internet
Websitemathworld.wolfram.com/StarPolygon.html" star polygon " of description.) generate star shape figure
Such alternate ways of case are herein defined as workable.
Liquid distributor
In various embodiments, the PCR- used in subsequent diagnosis is prepared using device described further herein
Sample is used, may include the one or more of the following steps:By the polynucleotides sample of neutralization with including polymerase and multiple
(in some embodiments, PCR reagent mixture can include further positive control for the PCR reagent mixture contact of nucleotide
Plasmid processed and be selective fluorogenic hybridization probe at least part plasmid);In some embodiments, PCR reagent is mixed
The forms presence that one or more beads can be lyophilized in object is closed, in the storage of storage on the holder, and the method can
To further comprise PCR beads and liquid reconstruct to generate PCR reagent mixture solution.It is multiple, it is such as one or more, with
The related liquid of above-mentioned steps transmits operation and can be realized by aupette head.
Include for the suitable liquid distributor that device herein uses:One or more sensors;Manifold;With it is described more
One or more pumps of branch fluid communication;With one or more dispensing heads of the branched fluid communication;It is controlled with from outside
Device processed receives the electrical connection of electric signal, wherein the liquid distributor other than by one or more pumps, is not used to flow
The entrance of body or outlet.
The viewgraph of cross-section of exemplary liquid distributor is shown in figure 18.Liquid distributor is configured at two or more
It is carried out at the same time fluid on a fixator and transmits operation.As shown in figure 18, liquid distributor 2105 may be mounted at tool there are three flat
It moves on the rack of degree of freedom.Other embodiments may include the rack having less than three translation freedoms.Mounting means
It can be by such as one or more screws of mechanical fasteners, as shown in Figure 18 left-hand sides.Suitable rack includes by coding stepping
Three axis of the band driving slide plate of motor drive.Rack slide plate may be mounted at structural point aluminium or other same materials
On frame, especially metal or metal alloy.Alignment x- and y- directions slide plate (be separately pointing to except the plane of Figure 18 and it
It is interior) promote rack crossing over a series of fixators and the movement on the direction along given fixator respectively.
The z-axis of rack can be connected with the sensor of variable force, and the sensor can be configured to pick up and flow in suction nozzle
The vertical movement degree of the head is controlled during body batch operation.As shown in Figure 18, for example, head of pipette 1803 can be in this way
Installation, so that the power acted on upwards for the head can be sensed by the relative motion between the head and force snesor.Example
Such as, it when disposable pipette is exerted oneself in head of pipette 1803 is for the holder below it, transmits upward power and causes head
1803 reverse around pivot location 2102, and positioning screw 2104 is caused to squeeze force sensor.Then, force snesor at least
Processor or the controller communication for controlling the vertical movement of liquid distributor, so as to therefore, appropriate when receiving from force snesor
When signal, processor or controller can send instruction to prevent the vertical movement of liquid distributor.What is be suitble to herein enumerates
Property force snesor can be obtained from Honeywell;Its explanation is shown in the annex of this paper.The force snesor shown in Figure 18
Mechanism is exemplary and many possible mechanisms during upper pickup (up pick up) and fluid batch operation one kind
The head can be controlled.For example, as force snesor an alternative it is possible to using when being contacted with sample cell or reagent fixator
The stall sensor of the interruption of the one or more dispensing head vertical movements of sensing.Therefore, as those of ordinary skill in the art manage
Solution, liquid distributor described herein are not limited to the concrete mechanism shown in Figure 18.
Liquid distributor further includes the head 1803 of certain amount independently bounced, wherein being configured to from fixator per head
One or more pipette tips receive pipette tip.Liquid distributor can be further configured in this way, so as to two
Head does not receive pipette tip from identical fixator.For example, Figure 19 A-C describe four heads 1803 independently bounced, but should
Understand that the distributor is not limited to the number.For example, other numbers include 2,3,5,6,8,10 or 12.Moreover, display is independent
The head 1803 bounced arranges in parallel to each other, but can be arranged with other.
Liquid distributor may further include the pump 2100 of computer control, is connected to and is controlled with correlation computer
Valve distribution manifold 1802.Distribution manifold 1802 may include the valve of certain amount, and it is logical to be such as configured to control
Cross the solenoid valve 1801 of the air stream of pipette tip:In exemplary embodiment, there are two to be used for each liquid relief
The other valve of the valve of pipe and a discharge pump.Thus, for having the liquid distributor there are four head of pipette,
There are nine valves.In another embodiment, there is only the valves that one is used for each pipette, and discharge the pump
Another valve.However, distribution manifold is not limited to include accurately nine solenoid valves.
Liquid distributor is further configured to extract out or distributes fluid, together with analyzing or prepare the molten of two or more samples
Liquid.Liquid distribution is also arranged to distribute the liquid in microfluid box.In addition, liquid distributor is configured in single operation
Receive or distribute 1.0ml or less Fluid Volumes, the Fluid Volume such as within the scope of 10nl-1ml.
Liquid distributor is configured so that, air is pumped into and is left distribution manifold to pump 2100.Distribution
Manifold is included in the Microfluidic networks that air is uniformly distributed in one or more valves.Thus, passed through by controlling air
The flowing of manifold and multiple valves, thus it is possible to vary the pressure on pipette tip, so as in liquid assimilating to pipette tip
And it is discharged from pipette tip, the pipette tip is connected to corresponding head of pipette.In this way, it is not necessary that warp
Air is supplied to liquid distributor by air hose.Also unnecessary to provide fluid pipeline to dispensing head.Moreover, from described solid
The liquid reagent or fluid sample for determining device do not enter any part that liquid distributor includes manifold.This respect reduction comes from will
Air bubble is introduced into the complication of sample or liquid reagent.The exemplary construction of distribution manifold is shown in fig. 20.
It is such as multiple as shown in the figure, it is self-contained unit in whole liquid distributors that z-axis moves up and down, only has
Electrical connection for processor or controller, and the mechanical connection for rack.The D translation movement of liquid distributor can be with
It is controlled by microprocessor such as processor 980.Fluid operation pipeline is not associated with distributor.This design can simplify instrument dress
Match, the sample cross contamination between instrumental pollution and the different operation situation of described device is made to minimize, increases pumping efficiency (most
Small dead volume) and easily can safeguard and repair described device.The arrangement can also be easy to improve in distributor
Feature such as individually connects or removes with each distributor of independent pump control, individual pipette, can control pipette
Screw pitch (pitch) etc..
The other side of described device is related to sample diagnostic test device, and be configured to examine the number contains nucleic acid
Sample the identity of each.Such sample diagnostic test device can be optical character recognition reader, bar code reader, or
RF tag reader or other suitable reader, as obtained by those of ordinary skill in the art.Sample differentiates inspection
It tests device to may be mounted on the rack, or is connected to liquid distributor so as to it and liquid distributor uniform movement.Alternatively,
Sample diagnostic test device can be independently mounted and can be moved independently of liquid distributor.In Figure 21 and 22, for example, sample
Judge the bar code reader that other verifier 1701 is attached to liquid distributor.The visual field of bar code scanner 1701 is non-thread
Property, enable it to detect being reflected by mirror 2300 in disposable holder 2302 bar code clinical sample pipe 2301
Light.Bar code on bar code scanner Read Clinical sample cell, thus identify presence and the details of sample cell.Due to mirror
It uses, scanner is configured to read the bar code (being thus reflected into normal form) of mirror image forms, or is configured to read normal
The mirror image of bar code and the mirror image is converted to unreflected form via computerized algorithm.
Sample diagnostic test device be configured to by after testing or read label details communicate in device processor or
Controller, therefore sample is allowed to identify information related with diagnostic result and other information related with sample preparation, and carry
Take and expand nucleic acid therein.
In fig 23, localizing sample diagnostic test device is with from microfluid box read flag.
In certain embodiments, liquid distributor can also include one or more sensors 2001 (for example, infrared biography
Sensor), the presence of pipette tip in each of which detection support.In fig. 24, for example, infrared sensor 2001 can have
Relative to the infrared transmitter that it is placed, and the presence of disposable pipette tip 2000 interfere transmitter and detector it
Between sight, it is possible thereby to measure the existence or non-existence of pipette tip.Pipette will be handled perpendicular to pipette stripper-
Aligning strip 2003 configures, as described further herein.
Liquid distributor can also be run together with motor-driven plate, and the motor-driven plate is configured to distributing a fluid to microfluid
Pipette is removed during box inside and harmonizes pipette, as described further herein.
Figure 25 A and 25B show the example for removing pipette tip from liquid distributor as described further herein
Act property device.All in identical pitch, pipette tip is aligned in fixator (pipette tip set on corresponding jack
On).Metallic plate with elongated pore is located on jack.Pipette tip is inserted downwardly into the set by elongated pore part way
In, and metallic plate moves forward in such a way, and the mode is that pipette tip is pressed from both sides by the prolongation in the hole
Firmly.When liquid distributor moves up, pipette tip becomes head corresponding to they and separates.When metallic plate then moves back to
When to its initial position, pipette tip is maintained at the position of their corresponding jack.
Heater assembly and magnetic separator
The viewgraph of cross-section of the unit heater of exemplary heater assembly 1401 is shown (right version) in figure 18.Heater
Component includes one or more independently controllable unit heaters, includes each a heat block.In certain embodiments,
There are 2,3,4,5,6,8,10,12,16,20,24,25,30,32,36,40,48 or 50 heater lists in heater assembly
Member.The unit heater of also other numbers, arbitrary number between such as 6 to 100 are consistent with description herein.One or
Multiple heat blocks can be made of unitary piece of metal or other materials, or can manufacture independently of each other and install independently of each other or
It is connected with each other in some manner.Term heater assembly refers to the integrated of unit heater as a result, but does not need heater
Unit or their corresponding heat block are directly or indirectly connected with each other.Heater assembly can be configured so that, so as to each heating
Each of device unit independent heating one or more processing tube 1402, for example, by make one or more heat blocks each
Be it is independently controllable, as described further herein.In the construction of Figure 26, heater assembly includes one or more heats
Each of which is configured to harmonize and transfer heat to processing tube 1402 by block 1403.Use item 1408 and one or more spiral shells
1407 or other bonders are followed closely, each heat block 1403 can optionally fix and be connected to the rest part of device.This is tight
Gu mechanism is not limited to such a construction.
Although the viewgraph of cross-section of a heat block 1403 is shown in fig. 26, it should be understood that this with being mutually parallel
The multiple heat blocks harmonized are consistent, and therefore their geometry midpoint is entirely located on single linear axis, although it is without such as
This is limited in construction.As a result, one or more heat blocks can in groups or alternatively, be independently positioned at it is mutually different
Height, or can in groups or alternatively, independently interlock (right version) relative to each other from left to right in fig. 26.In addition,
And in other embodiments, heat block is not harmonized in parallel to each other, but with angle configurations relative to each other, the angle
Degree is not 180 °.Moreover, although the heat block shown in Figure 26 can be that size is identical one of several, with skill herein
Art is compatible, and one or more heat blocks can be configured to receive and heat various sizes of processing tube.
Exemplary heat block 1403 (right version) is configured to the inner cavity around the lower part of processing tube 1402 with part in Figure 26.
In the heat block of Figure 26, the inner cavity surrounds the lower part of processing tube 1402 in both sides, rather than front side is (away from magnet
And not rear side (being adjacent to magnet 1404) 1404).In other embodiments, heat block 1403 is configured to three sides
Face surrounds the bottom of processing tube 1402, including front side.With the rapid and uniformly heated mesh for the content for realizing processing tube 1402
Mark is consistent, and other constructions of heat block 1403 are possible.In certain embodiments, heat block is shaped to closely conform to locate
The shape of pipe 1402 is managed so that increasing the heat block surface area contacted with processing tube during processing tube heats.Although showing as a result,
Show that exemplary heat block 1403 has circular cone, curve bottom cavity, wherein fixed complementary processing tube, but heat block
1403 other embodiments have, for example, having flat cylindrical cavity.Other embodiments of heat block 1403 can
Will such as accommodate cuvette with straight inner cavity.
Moreover, although heat block 1403 is shown as L- shapes in fig. 26, auxiliary transmission is from heating element 1501
One or more heat blocks are fixed to the rest part of described device by heat and auxiliary, but it is not necessarily in this way, such as this
What text was further described.For example, in some embodiments, heating element 1501 can be positioned directly under processing tube 1402
Face.
Each heat block 1403 is configured to the thermal mass for having low, while still maintaining high structural intergrity and allowing
Magnet easily slides past heat block and processing tube.Low thermal mass is advantageous because it allow heat rapid delivery or
Dispersion, thus increases the wherein heating of the device of position heater component and cooling efficiency.Promote low thermal mass factor include
Heating is by what material manufacture and shape that it takes soon.Therefore heat block 1403 can be made of such material,
Such as aluminium, silver, gold and copper and its alloy, but do not limit so.
In one embodiment, heat block 1403 with~10 grams of quality and is configured to heating volume in 1.2ml
And 10 fluid sample between μ l.65 DEG C are heated to for 1ml biological samples from room temperature to realize in less than 3 minutes, and
And 10 μ l waterborne liquid such as discharge buffer solution in less than 2 minutes up to 85 DEG C (from 50 DEG C).Heat block 1403 can be
In less than 3 minutes 50 DEG C are dropped to from 85 DEG C of coolings.Heat block 1403 can be configured to have temperature uniform in heating 1ml samples
Property be 65 ± 4 DEG C, and it is 85 ± 3 DEG C to have temperature uniformity for 10 μ l release buffer solutions of heating.These ranges are typical
, but heat block can be compatibly scaled to more other than those described slower and faster rate heating
The liquid of volume.This aspect of the technology is contributed to through liquid processing steps, the rapid heating of lysis, DNA captures
With release and the combination of Magnetic Isolation, the one side of the Rapid nucleic acid extraction of multiple samples is realized, as institute is further herein
Description.
It is not shown in Figure 26, heater assembly 1401 can also be optionally included in the shell of heat block 1403.Institute
It states shell to can be configured to that enough air is made to flow around processing tube, and so as not to significantly inhibit cooling rate.It is described
Shell can have gap to promote to cool down at it between heat block.The shell can be made of plastics, but without such as
This limitation.The shell is usually configured to appear to be beauty for user.
As shown in Figure 26, heater assembly 1401 can also include one or more heating elements (for example, power resistor
Device) 1501, each of which is configured to be thermally connected to heat block 1403 and heat is distributed to it.For example, in an embodiment party
In case, power resistor can disperse up to 25 watts of power.Power resistor is advantageous, because it is usually heating element
Low cost alternative.The other electronic component that can be purchased off the shelf such as power transistors can be used for sensing temperature and add
Heat.Although display heating element 1501 is placed on the bottom of heat block 1403, but it is to be understood that other constructions are retouched with this paper
The component stated is consistent, for example, heating element 1501 can be placed on the top or side of each heat block 1403, or located immediately at
Below processing tube 1402.In other embodiments, heating element has other shapes and is not rectangular on cross section
Shape, but can be bending, such as spherical or elliposoidal.In addition, heating element can be molded or be molded so that it is close
Or approximately conform with the shape of processing bottom of the tube.It does not show in fig. 26, the heater assembly can also be in heating element 1501
Including boundary material (for example, Berquist q- pads or hot grease) so as in element and add between heat block 1403
It is well thermally contacted between heat block.
In embodiment shown in fig. 26, heater assembly further includes one or more temperature sensors 1502, all
Such as resistance temperature detector, to sense the relevant temperature of each heat block 1403.Although displays temperature sensor 1502 is placed on
The bottom of heat block 1403, but it is to be understood that other constructions are consistent with components described herein:For example, temperature sensor
It can be placed on the top or side of each heat block 1403, or closer to the bottom of processing tube 1402, rather than so connect
Closely so that it is prevented to be evenly heated.As shown in the embodiment of Figure 26, heater assembly can also include boundary material (example
Such as, Berquist q- are padded) 1503, it is configured to well thermally contact between sensor 1502 and heat block 1403, because
This ensures accurate read.
Certain embodiments of diagnosis or preparation facilities herein have more than one as described further herein
Heater assembly.For example, single heating device assembly can be configured to independent heating 6 or 12 processing tubes, and device can match
It is equipped with heater assembly as two or four.
Content disclosed herein further comprises magnetic separator, is configured to separating magnetic particles, and the separator includes:
One or more magnets fixed to support component;It is configured to move the motor-driven mechanism of support component in this way, it is described
Mode is that one or more magnets are rearwardly and a forwardly moved along fixing axle, and during at least part is mobile, described one
A or multiple magnets are kept close proximity to one or more storages containing the magnetic-particle in solution;With control motor-driven mechanism
Control circuit.
Content disclosed herein is further including integrated magnetic separator and heater, including:Heater assembly, wherein
The heater assembly includes multiple independently controllable unit heaters, each is configured to receive and heat multiple processing tubes
One;One or more magnets fixed to support component;It is configured to move the motor-driven of support component in such a way
Mechanism, the mode are that one or more of magnets are rearwardly and a forwardly moved along fixing axle, and are moved at least part
During dynamic, one or more of magnets are kept close proximity to one or more of heater assembly processing tube, wherein institute
It states one or more processing tubes and contains magnetic-particle;It is electric with controlling motor-driven mechanism and controlling the control that unit heater heats
Road.
Usually, each of one or more storages is processing tube, such as carrying out biological respinse.In some implementations
In scheme, there is the face less than 2mm far from processing tube outer surface close to magnet can be limited to, do not connect with the pipe
It touches.It can further be defined as the distance less than 1mm, without being contacted with the pipe, or between 1 and 2mm distances.
Usually, the magnetic-particle be can in conjunction with the particle of one or more biomolecule such as polynucleotides, pearl, or
Microballoon.The particle is detached in the solution, is generally included the powder collection and concentration, or gathers one or more storages
In a position inside device.
Exemplary magnetic separator 1400 is shown in figure 27, is configured to run together with heater assembly 1401.It is magnetic
Separator 1400 is configured to move one or more magnets relative to one or more of processing tubes 1402.Although being shown in Figure 27
The magnet 1404 shown is shown as rectangular component, but what it was not so limited in shape.Moreover, the construction of Figure 27 with
With the single magnet extended on whole heat blocks 1403 or with operate together and harmonize with cross over heat block subset, example
Such as, the multiple magnets collinearly harmonized on a support element are consistent.Magnet 1404 can be by neodymium (for example, coming from K&J
Magnetics, Inc) it is made, and can be with the magnetic intensity of 5,000-15,000 Gauss (Brmax).The magnetic of magnet 1404
It can extremely be arranged such that, so that a magnetic pole is towards heat block 1403 and another is away from heat block.
In addition, in the embodiment shown in figure 27, magnet 1404 is mounted on support component 1505, can be used
Motorized shaft 1405 increases up and down along fixing axle.The fixing axle can be vertical.In the embodiment shown in figure 27,
Gear-driven arrangement 1406 can be such that motor 1601 is placed perpendicular to axis 1405, therefore save and wherein position magnetic separator
Space in 1400 device.In other embodiments, motor is placed below axis 1405.It should be appreciated that other structures
It is consistent relative to processing tube movement with magnet to make, and is included, but are not limited to from side to side moving magnet, or make magnet
From top to bottom.Motor can be computer control to run at a given speed;Such as to cause in range 1-20mm/
The rotating speed of the magnet vertical movement of s.Magnetic separator can be thereby configured to move repeatedly for several times along same axis, for example, on
Under, from side to side, or rearwardly and a forwardly.In some embodiments, there is more than one operated under maneuver autopilot
Axis.The presence of at least the second axis has the effect of keeping separator movement smoother.In some embodiments, support component is pacified
Be placed on more than one directed element, with ensure support component during exercise (in addition to the controlled motion along axis) will not,
For example, tilting, twisting, deflecting, or undergoes other internal motions and therefore reduce separation effect.
The support component may be configured in first position far from the positioning of one or more of storages and close
Moving magnet between the second position positioned close to one or more of storages, and be configured to surround described second
The amplitude of position moves, wherein the amplitude is less than when being measured along the axis between the first position and the second position
Distance.
It is shown in Figure 26 and 27, heater assembly 1401 and magnetic separator 1400 can pass through such as printed circuit board
Electronic circuit control on 1409.Electronic circuit 1409 can be configured to that heater assembly 1401 is made to be apply independently to locate by heat
Pipe 1402 is managed so that heating and sensing cost minimization.It may be configured to cause magnetic separator 1400 relative to processing tube
1402 move repeatedly.Electronic circuit 1409 is desirably integrated into single printed circuit board (PCB).In period of assembly, plastic guide
Piece can assist in keeping some spacing between independent heat block 1403.The design can benefit from using the electronics that can be purchased off the shelf
Instrument is to control the customized arrangement of heat block 1403.
It is not shown in Figure 26 and 27, the protection for following sub-component and beauty, shell can cover magnetic separator
1400 and heater assembly 1401.Shell is also designed to that heat block 1403 is kept to be located remotely from each other interval to ensure to add hot and cold
But efficiency.Magnetic separator and heater assembly can be with alternatively, by individual shell seals.One or more shells can
To be made of plastics.
Advantageously, heater assembly and magnetic separator are run together to allow continuously to heat with lock out operation at one
Or carried out on the fluent material in multiple processing tubes, without fluent material or processing tube are transported to different location to execute heating
Or separation.Such operation is also advantageous, although as it means that heating and separation function independently of each other, all use
In sample preparation, it can be carried out with compact and effective device.
The automatic loader of box
It is shown in Figure 28 for the exemplary embodiment of PCR amplification-detecting system 2900 used in microfluid box.System
System 2900 is executed and is automated with making the PCR process parallels on multiple samples containing nucleic acid.System 2900 includes for not
The storeroom 2907 of the microfluid box used, the automatic loader of box, for the compartment that receives of microfluid box, detector, and
It is configured to receive the waste material disk 2903 of used microfluid box.In one embodiment, the automatic loader of box includes box
Packaging 2901 and box propeller 2904.
For illustrative purposes, system 2900 is configured so that, so that microfluid box is in one plane and with straight
Line mode is moved to from storeroom receives compartment, arrives ash can, but its not necessary arrangement.For example, discarded carton and crate 2903 can be with
Orthogonally or its any angle adjustment receives compartment, such as configures behind it.Alternatively, each element (automatic loader of box
2901, receive compartment 2902 and discarded carton and crate 2903) can be configured in a manner of step condition, wherein box packaging 2901 be with
Microfluid PCR amplification-detecting system 2902 is compared to identical, and in higher or lower level, and microfluid PCR expands
Increasing-detecting system 2902 is identical compared with discarded carton and crate 2903, in higher or lower level.Another construction can
To be, each of three elements is not linearly aligned, to mutually include an angle ground, although within same level.
Figure 28 is illustrated in box packaging 2901 and the discarded carton and crate 2903 received below compartment plane, and side on the plane
Detecting system 2908.The construction is exemplary and should understand that these elements can be positioned in other embodiments
Above or below the plane.
Figure 29 illustrates the storeroom used in not used microfluid box.The storeroom can be configured to receive a fixed number
Purpose individual stacked and the box independently loaded, or can be configured to receive the packaging of box.Exemplary box packaging has 24 boxes.
Storeroom can be made of the cover 2910 of any material, can be or can not be transparent.Such as it can by metal or
Plastics are made.Box packaging 2901 is not limited to 24 boxes 106/ and packs, but can contain any number from 2 to 100.
For example, the box 106/ that other numbers such as 2,4,8,10,12,16,20,30,36,40,48,50 or 64 are possible numbers is packed.
Similarly, storeroom can be configured to receive the box of those numbers, when individual stacked.In one embodiment, such as scheming
In 29, each box 2906, individual stacked, it is located at from the protrusion 2911 that cover 2910 stretches out.However, other constructions are can
Can.For example, box 2906 can rest on the groove formed in the inner surface of cover 2910.Moreover, box packaging 2901 may not
It needs in cover 2910.Box packaging 2901 can itself include necessary connection to be securely joined to described device to load
The box 2906.
Figure 30 is when in the uppermost box that sample is loaded in packaging, and box packaging 2901 is exemplary first in storeroom
The explanation of beginning " loaded " position.Figure 30 is shown in the packaging of the box below plane 2901, contains box propeller.In other embodiments
In, box packaging 2901 can be on the plane of box propeller, wherein the propeller releases minimum box from fixator;Or
Part is on fixator 2920 and part is under fixator 2920, and wherein box propeller packs box in 2901 from box
Centre promotes.In the embodiment of display, uppermost box 106 is promoted along two guide rails 2905.It is alternatively possible in the presence of
More or fewer guide rails (such as one or three) or at all without guide rail, as long as it is other required that box 2906 can be made to be moved to
Position.
Exemplary box propeller 2904 is shown in Figure 31.Box propeller 2904 promotes box 2906 along guide rail 2905,
It allows box 2906 to be moved to the position of pre-calibration by the mechanism of stepping motor 2930.It will be appreciated, however, that delivery cartridge 2906
Mechanism be not limited to stepping motor 2930 and thus other mechanisms are also consistent with box propeller described herein 2904.
Figure 32 shows used box 2906, has been advanced to by box propeller 2904 after PCR processes have been completed
In discarded carton and crate 2903.Embodiment shows the handle 2940 of flange, promotes readily operation, such as empties, case 2903.So
And, it should be understood that handle 2904 is not limited to the form and shape of display.
Exemplary box packaging 2901 before and after multiple PCR processes are realized is shown in fig. 33.In box propeller
After box 2906 is released box packaging 2901 by 2904, promoted simultaneously against the lower surface that box stacks in the spring 2950 of box package base
And uppermost box is allow to be used in sample injection.Spring 2950 does not limit in number or type.Although display is single as a result,
Helical form or the spring of coiling, but it is consistent with description herein, that is, more than one helical form or coiling can be used
Spring, such as 2,3 or 4, and it is alternatively possible to use resilient metal strip or several.Alternatively, for forcing the box
Another upward mechanism can be expansion, can utilize it is such as wind-force, hydraulic pressure or can tympanites pressurized container.
It should be noted that microfluid box described further herein, the microfluid box has along their edge
There is the flange of protrusion to allow to be easy to stack and/or be stored in packaging or automatic loader, is particularly advantageous, because raised
Flange also rigidity is introduced into the box, and the fluid inlet assisted in keeping on a box during storage and transport is remote
From the fluid inlet on another box.Elevated regions are not necessarily only the flange along each edge of box, also help to make a box
Friction between lower surface and the upper surface of another box minimizes.
Receive the compartment of box
The prior art be related to for expand and on the nucleotide for come biological sample carry out diagnostic analysis device and
Correlation technique.Device is configured to work on the disposable microfluid box for parallelly containing multiple sample channels, and
And include the instrument platform that can be reused, can to start when being operated on box, can in each channel independently, it is all same
Shi Di detects and analyzes pcr amplification product group by group simultaneously, and it is optionally possible to is shown in the user interface of diagram
Show result.
Figure 34 shows the perspective view of the exemplary box 200 containing multiple sample channels, and believes containing being useful for reading from box 200
Number detection device exemplary read head 300.It is also shown in Figure 34, disk 110, optionally, receives compartment box to be inserted in
Before, disk 110 can be with accommodating case 200.Apparatus described herein can be carried out at the same time reality in box 200 on certain amount sample
When PCR.Preferred number of sample is 12 samples, as illustrated with exemplary box 200, although other numbers such as 4, and 8,10,
16,20,24,25,30,32,36,40 and 48 samples are within the scope of this specification.In the preferred operations of described device
In, PCR- be containing sample and, optionally, the solution of one or more analyte specific reagents (ASR's) uses dress
The other elements set are introduced into box 200 later as described further herein.
In some embodiments, device includes the compartment for being configured to selectivity and receiving microfluid box;Thermally coupled
(thermally couple) arrives at least one heat source of the compartment;And it is coupled to processing as described further herein
Device, wherein the heat source is configured to heat the independent sample channel in the box, and processor is configured to control for independent
The applying heat of sample channel, independently, all simultaneously, or simultaneously group by group.
In some embodiments, device further includes being examined in the sample being configured in one or more individually sample channels
At least one detector of polynucleotides (nucleic acid) is surveyed, separately or simultaneously;The wherein described processor is coupled to the detection
Device receives signal with control detector and from detector.
Compartment can be arranged to the part that selectivity receives the device of microfluid box.For example, compartment and micro flow
Body box can be complementary in shape for example to receive microfluid box with single-orientated selectivity.For example, described microcosmic
Fluid box can have the recording element being cooperated in the complementary characteristic of the compartment.Recording element can be, for example, box edge
On cut-out, the angle being such as cut out, or one or more nozzles for being manufactured on one or more sides.It is connect by selectivity
By the box, compartment may help to user and place the box so that described device can suitably be run on the box.With
The error free adjustment of box may be implemented in this method.Moreover, the box can be designed to slightly less than receive compartment about 200-
300 microns, being easily placed and removing for the box.Described device can also include whether being configured to sensing microfluid box
The sensor selectively received.
The compartment may be configured to it is such, so as to the multiple element of the device run on microfluid box
(heat source, detector, power element, etc.) be positioned to correctly run on microfluid box.For example, contact heat source can position
In the compartment, so that it can be thermally coupled to respective location in microfluid box, the microfluid box is selectively connect
By in receiving compartment.
Alternatively, need heat with corresponding together with the micro-heater in heater member micro element (such as valve,
Pump, door, reative cell etc.) adjustment, micro-heater can be designed to than needing the microfluid element of heat slightly greater, so as to
Even if the box can deviate the center of heater, individual component still can effectively work.
Detector 300 can be, for example, fluorescence detector, as described further herein.For example, the detector can
To be included in the light source of the absorption band selectively transmitting light of fluorescent dye, and the emission band selective enumeration method in fluorescent dye
The photodetector of light, wherein the fluorescent dye corresponds to fluorescence polynucleotide probes or its segment.Alternatively, for example, optics
Detector may include in the absorption band selectively bandpass filtering diode of transmitting light of fluorescent dye and in fluorescent dye
The bandpass filtering photodiode of emission band selective enumeration method light;Or for example, the fluorescence detector can be configured to independence
Multiple fluorescent dyes with different fluorescence emission spectrums are detected, wherein each fluorescent dye corresponds to fluorescence polynucleotide probes
Or its segment;Or for example, the fluorescence detector can be configured to the independent detection on multiple and different positions of microfluid box
Multiple fluorescent dyes, wherein each fluorescent dye corresponds to fluorescence polynucleotide probes or its segment in different samples.
Heat source can be, for example, the heat of such as heat source of resistance heater or resistance heater network, such as liquid filling
The reversible heat source of transfer circuit or thermoelectric element, the radiant heat source etc. of xenon lamp.
In preferred embodiments, at least one heat source can be selected from resistance heater (or its network), radiator, stream
Contact heat source of the heat exchangers with peltier device.Contact heat source can be only fitted to receive compartment so as to be thermally coupled to it is described every
One or more respective locations of the microfluid box received in room, wherein the different location selectively heats.It can be with
Including at least one other contact heat source, to be independently thermally coupled to connect in compartment wherein the contact heat source is individually configured in
The compartment of different respective locations in the microfluid box received, wherein the respective location is independent heating.Contacting heat source can
To be configured to the respective location direct physical contact with the microfluid box received in compartment.In various embodiments, each
Contact source heater can be configured to heating respective location, and the respective location has about 1 millimeter (ibm) to about in 2 dimensions
The average diameter of 15mm (being typically about 1mm to about 10mm), or heating respective location, the respective location have about 1mm2Extremely
About 225mm2(it is generally about 1mm2To about 100mm2, or in some embodiments, about 5mm2To about 50mm2) surface area.
In various embodiments, at least one heat source can be radiant heat source, and the radiant heat source is configured to directly add
Respective location of the heat to the microfluid box for receiving to receive in compartment.
In various embodiments, described device includes one or more power elements, and the power element is configured to apply
Power so as to the microfluid box for being thermally coupled to receive in compartment by least one heat source at least part.One or more power members
Part can be configured to run mechanical organ in microfluid box.At least one power element can manually be run.It is at least one
Power element can receive compartment mechanical coupling to lid, and the wherein operation of lid runs the power element.
In various embodiments, the power applied by one or more power elements can be in the part that receives compartment and micro-
See the average pressure that the interface between a part for fluid box generates about 1psi.For ensuring in heater chip and microfluid box
In PCR reactors and micro-valve door between consistent thermo-contact, the application of power is important.
In various embodiments, described device can further comprise that lid, the lid are can to grasp receiving compartment
Make, to exclude ambient light at least partly from the compartment.The lid can be, for example, the lid of sliding.The lid
Son may include fluorescence detector.It can be sexually revised from plane less than about 100 microns in the major surfaces of the lid of compartment, such as
Less than about 25 microns.The lid is configured to moveable from described device.The lid may include blocking element,
It ensures to be applied in box before sample in amplified reaction, and the lid is reliably closed.
Figure 35 shows the schematic cross-sectional view of a part for apparatus described herein, and display sample is via being attached to
The pipette tip 10 (such as disposable pipette) and entrance 202 of automatic dispensing head are input in box 200.Although not showing
Show there is the entrance 202 as many with the sample that be input in box 200.Entrance 202 be preferably arranged to receive pipette or
The bottom end of PCR pipe, and therefore receive the sample for being used to analyze in the case where minimum waste material and minimum air introduce.Box 200
Configuration is upper at 400 top of heater base and is contacted with heater base 400.Read head 300 be located on box 200 and
The amount for the ambient light that the limitation of covering 310 for optical device can be detected by read head.
In various embodiments, system as described herein may include both microfluid box and diagnostic device.
Microfluid box
The one side of the technology of the present invention is related to microfluid box, and the microfluid box includes first, second and third
Layer, limits multiple Microfluidic networks together, and each network has the multiple element for being configured to that PCR is carried out on sample, institute
Its existing one or more polynucleotides will be measured by stating sample and having.The box includes parallel one or more samples
Channel, wherein each channel is independently connected with the given sample handled simultaneously, and the micro- of separate configurations is contained in each channel
See fluid network.The exemplary box having a structure in which is shown in Figure 36.Such box is simple to manufacture, and allows to concentrate
PCR in reaction volume (~4 μ l) and can rapid thermal cycle, with~20 seconds/cycle.
Although other layers, box herein can be found in the box with comparable performance and ease of manufacturing
It include the embodiment only in their structure with three layers:Base with upside and opposite downside, wherein the base
Layer includes the Microfluidic networks with multiple sample channels;The laminated material of downside is connected to seal Microfluidic networks
Element, and the special heating element in Microfluidic networks and effective heat transfer layer is provided between element;And label, it is described
Label is connected to upside, the upside also cover and seal in manufacturing process to load microfluid element such as valve and
The hole used.Thus, embodiment herein includes the microfluid being made of three layers, base, laminated material and label
Box, although the feature other, in addition in addition to layer can be compatible with such characteristic.Embodiment herein further includes base
The microfluid box being made of three layers, base, laminated material and label on this, although the spy other, in addition in addition to layer
Sign can be consistent with such characteristic.Moreover, embodiment herein further includes three layers, and base, lamination
Material, and label microfluid box.
Microfluidic networks may include, with fluid communication, selected from consisting of the following group of one or more member
Part:Gate (gate), such as valve of thermal starting valve, channel, floss hole and reative cell.Exemplary Microfluidic networks
Particular element is further described through other places in this article.The box is generally by increasing polynucleotides concentration to be determined
Handle sample.
Sample channel is a set of pieces, can be retouched according to this paper independently of what is controlled those of in another sample channel
The method stated can be received by it and analyze sample.Channel includes at least one sample inlet and microfluid element, such as this
Text is further described about microfluid box.In some embodiments, each Microfluidic networks also comprise overflow
Reservoir is to contain the extra liquid being assigned in the box.
In various embodiments, channel may include sample inlet, the valve of the first thermal starting, the valve of the second thermal starting
Door, PCR reative cells, and entrance is connected to via the first valve the channel of PCR reative cells, and via the second valve by PCR
Reative cell is connected to the channel of outlet drain mouth.Sample inlet valve can be configured to about 100 arrive compared with environmental pressure
The pressure difference of 5000Pa receives a certain amount of sample.It should be noted that loading, pressure is lower, the aliquot filling of reaction mixture
The filling time of Microfluidic networks is longer.The filling time will be reduced by applying bigger pressure, but if stressed for applying
Time incorrect measurement, then sample may be sprayed (if terminal hydrophobic floss hole is not present) by microfluid box.Therefore, it uses
It should suitably be measured in applying the stressed time, such as the method as obtained by those of ordinary skill in the art, to prevent
Only underfill or over-fill.In general, the filling time is inversely proportional with solution viscosity.For example, Figure 37 show containing can it is independent (while or
Sequentially) the microfluid box in 12 independent sample channels of processing sample.
Microfluidic networks in each channel are generically configured to carry out PCR, the sample on PCR- samples i.e.
Such as contained using the other aspects of device as described further herein extracted from original biological specimen nucleic acid (DNA or
RNA sample).Thus, it is usually the polynucleotides sample for including one or more PCR reagents and neutralization that PCR-, which is with sample,
Mixture is suitable for the thermal cycle conditions for carrying out generating PCR amplification from the polynucleotides sample of neutralization.For example, PCR- is used
Sample may include PCR reagent mixture comprising polymerase, positive control plasmid, at least part of plasmid and more
A nucleotide is selective fluorogenic hybridization probe, and is selective at least one probe for polynucleotide sequence.
Usually, Microfluidic networks are configured so that, so that sample droplet is transmitted to from entrance needed for the second valve
Time be less than sample move the time required to outlet drain mouth 50%.Usually, Microfluidic networks are designed to
Two valve downstreams have increased flow resistance, compared with the amount being filled into needed for network end-point floss hole from the first valve,
The total volume of Microfluidic networks is not increased.
Figure 38 A show the perspective view of a part for the exemplary microfluid box 200 according to the technology of the present invention.The box can
To be known as the multichannel PCR boxes with special liquid relief tube inlet 202.Multiple typical elements of box 200 are shown in Figure 38 A.
For example, sample inlet 202 is configured to receive syringe, pipette, or containing PCR be the PCR pipe with sample.It shows more than one
Entrance 202, one of entrance together with single channel operate.Each the multiple element of the microfluid pipeline in channel is also
It is visible.For example, micro-valve door 204 and 206 and floss hole 208, are to the part of the microfluid pipeline in routing.It is also aobvious
Ultrafast PCR reactors 210 are shown, as described further herein, this is sufficiently long microfluidic channels to allow PCR in sample
Occur in product.On PCR reactors 210 is window 212, when detector is located at 212 top of window, the window 212
Allow the optical detection in PCR reactors 210, such as fluoroscopic examination from fluorescent material, the fluorescent material such as fluorescence
Hybridization probe.
Multichannel box is configured to receive the sample of certain amount, is 12 samples, wherein institute in specific embodiments
It includes at least one first sample and at least one second sample to state sample, wherein first sample and second sample are each
From the one or more polynucleotides contained suitable for amplification form.In the different channels of box, the polynucleotides can phase
It is mutually identical or different.Multi-example box includes at least one first Microfluidic networks and at least one second Microfluidic networks,
They are mutually adjacent, wherein each of the first Microfluidic networks and the second Microfluidic networks such as institute elsewhere herein
Description, and wherein described first Microfluidic networks receive the first sample, and wherein described second Microfluidic networks connect
By the second sample.
The sample inlet of adjacent channel is suitably spaced from each other, to prevent from introducing the sample into any one as user
When in a box, any pollution from another sample of a sample inlet.In some embodiments, such as by sample inlet
This configuration is to prevent after a sample is introduced into the channel, by later sample because carelessness is introduced into
Given channel.
In some embodiments, Multi-example box has substantially the same with conventional use of 96- orifice plates in this field
Size.Advantageously, then, the box can be used together with the sheet processor that elsewhere in the art uses.However, more excellent
Selection of land, design Multi-example box are 9mm so as to the spacing between sample inlet barycenter, this is the standard that industry is assert.It means that
In certain embodiments, the distance for receiving the center to center between the ingate of the box of sample from PCR pipe, as herein institute into
The description of one step, be 9mm.The frustoconical shape with appropriate cone angle is made in ingate, so as to industrial standard
Pipette tip (2 μ l, 20 μ l, 200 μ l, volume, etc.) be closely fit with, enter from the widest point of entrance.Thus, in certain realities
It applies in scheme, entrance includes the reversion frusto-conical configuration of at least 1mm high, and receives what pipette tip entered at it
Widest point has the diameter of 1-5mm.Device herein can be complied with to be suitble to others subsequent occurrences of not herein
In the industrial standard of pipette tip that in addition describes.Usually, receive to enter the microfluid in sample channel via entrance
The sample volume of network is 1-20 μ l, and can be 3-5 μ l.Within the cone of ingate, ingate can be designed to tightly
Close fit pipette tip and around pipette tip generate excellent sealing.However, cone is designed in this way, to seal
It is reversible, because if sealing is too tight, so that, when pipette tip is elevated, the box can be with after batch operation
Far from it disk or receive position in compartment and pull out, this is undesirable set of.
Figure 37 shows the plan view of the exemplary microfluid box with 12 channels.Ingress port has 6mm spacing, with
Just, when being used together with the automatic sample loader with 4 heads, equidistant apart 9mm can be with three batches of every batch of 4
Entrance described in entry load:For example, entrance Isosorbide-5-Nitrae, 7 and 10 together, is then finally 3,6,9 followed by 2,5,8 and 11, and
12, wherein 12 entrances are from the side of box to other side serial number.
Figure 39 A are shown in the typical micro flow found in a channel of the multichannel box shown in such as Figure 38 A and 38B
The plan view of body pipeline.Figure 39 B are shown in another allusion quotation found in a channel of the multichannel box shown in such as Figure 36
Another plan view (left version) of type microfluid pipeline, and show how pipeline is visible (right version) by box structure.It is micro-
The other constructions for seeing fluid network will be consistent with the function of box described herein and device.In order, sample is passed through into liquid
Entrance 202 introduce, and optionally flow into bubble removal discharge-channel 208 (its be allowed in entrance during be introduced in sample
In the raw bubbles escape of idol), and continue along channel 216.Usually, when the automation distributor using fluid sample
When, capacity distribution is enough to accurate, so that bubble formation is not a notable problem, and the presence of discharge-channel 208 is not
It is necessary.
In all operationss of box 200, fluid is by as droplet actuator (be not shown in Figure 39 A, B in).204 He of valve
206 are shown as double valve in Figure 39 A, and the either side that channel therein is positioned at them has thermal response material (also referred to as temperature
Degree response substance) source.However, valve 204 and 206 any one or both can be side only in respective channel have heat
The single valve in responsive materials source.Valve 204 and 206 is initially to open, so that the droplets of fluid containing sample can be from entrance
Hole 202 is pumped into PCR reactors 210.When handling beginning, the detector being present in PCR reactor heads examines PCR anti-
The presence for answering liquid in device is then shut off valve 204 and 206, in either side from the channel separation PCR reaction mixtures.
PCR reactors 210 are by a series of hydronic microfluidic channels to carry out sample nucleotide
Amplification, as described further herein.Usually, PCR reactors have the volume that 3-5 μ l are especially 4 μ l.In PCR reactors
The inner wall in channel be made to during manufacture it is very smooth and be polished to bright finish (for example, using SPI A1 are selected from,
The polishing of SPI A2, SPI A3, SPI b1 or SPI B2).This is to be trapped in any micro- of PCR reactor surfaces
Visible air minimizes, and will cause to blister during thermal cycle step.Bubble is especially the detection zone in PCR reactors
In presence can cause PCR react misread.Moreover, PCR reactors 210 are made it is shallow so that crossing channel depth
Temperature gradient minimizes.Allow detector monitors reaction process and also detect in the region of box 212 on PCR reactors 210
Fluorescence from the probe for being attached to a certain amount of amplification of nucleotide.Region 212 is made of the thinner material of the rest part than box,
So as to allow PCR reactors for heat cycles be it is more reactive (for example, be suitable for denaturation and annealing steps temperature
Between quickly heat and cool down), and so that reduce dazzle, the taken in excess of autofluorescence and fluorescence.Thermal cycle it
Before, what valve 204 and 206 was both closed, to prevent any evaporation of liquid, bubble from generating, or from PCR reactors
Fluid motion.
End floss hole 214 prevents user that any excessive liquid is introduced into microfluid box, and plays limit
Make the effect that is not intended to part of any sample leakage to the box.User can input small to filling bubble removal floss hole
The sample volume of amount to the amount in PCR reactors center, or other than valve 204 or valve 204.The use of micro-valve door prevents
The loss of both liquid or steam, therefore the reactor being partially filled with even is enable to successfully complete PCR thermal cycle reactions.Apply
Pressure (such as~1psi) makes box touch the heater of instrument, and help is realized more preferable between heater and the hot receiving portion of box
Thermo-contact, and be also prevented from the expansion of bottom laminate structures, this will send out under conditions of PCR channel parts are hydraulically full
It is raw, and the air retained will thermally expand during thermal cycle.
In multiple embodiments, Microfluidic networks can optionally include being attached at least one of end floss hole to dredge
Aqueous floss hole.
After PCR is carried out on sample, and have determined that polynucleotide of interest existence or non-existence, preferably
, the sample of amplification is maintained on box, and the box or reuses (if one or more channels keep opening),
Or jettisoning.If a user desire that the analysis after operation amplification, such as gel electrophoresis, user can pass through the laminated material of box
A hole is drilled, and recycles the PCR product of general about 1.5 microlitres of amounts.The individual channels PCR can also be placed on by user
In special narrow heating plate, it is maintained at the temperature of the wax in fusing valve, then by response sample from the entrance in the channels PCR
It extracts out in hole.
In various embodiments, Microfluidic networks optionally can be configured to the storage containing waste material including at least one
Device.
In various embodiments, the microfluid box may further include label, such as computer-it is readable or
Scannable label.For example, label can be bar code, RF tag, or one or more computer-readable or optics can
The feature of scanning.The label can be positioned such that, so that it can pass through sample diagnostic test described further herein
Device is read.
In various embodiments, during transport and storage, microfluid box can be surrounded further by hermetic bag.
Microfluid box can be sealed in the bag containing inert gas.Microfluid box can be disposable.
Microfluid box 200 can be according to requiring to make.Usually, microfluid box layer, which includes one layer, has presser sensor
The polypropylene of adhesive or other plastics label (generally about 50 to 150 microns of thickness), are configured to seal the loading of the valve
The hole of wax, the air that retention starts for valve, and the position marked with operator.This layer can be two independent pieces
Form, although it should be understood by one skilled in the art that in many embodiments, monolithic layer will be suitable.
Microfluid base layer, injection molding usually from plastics, preferably (cyclic olefin polymerize zeonor plastics
Object), there is the channels PCR and valve passage on the first side, and there is discharge in the second side (being configured against the label)
Channel and multiple ingates, including load hole and the liquid inlet orifice of wax.Usually, the whole of Microfluidic networks together, is wrapped
PCR reactors are included, the ingate for detaching PCR reative cells and valve are limited in single base.Base is by base and box
It assigns rigidity and for air or liquid is made of non-infiltrative material, so as to the air or liquid during box operates
Into or leave only possible through the entrance or floss hole.
The channel of Microfluidic networks in the channel of the box 200 generally cross sectional dimensions at least 1 submillimeter.Example
Such as, the channel of such network can have about 1mm or smaller (for example, about 750 microns or smaller, about 500 microns or smaller,
About 250 microns or smaller) width and/or depth.
The box may further include use, for example, thermal, pressure combines, or combinations thereof and be connected to micro flow
The heat-sealable laminate ply 222 (usually, about 100 to about 125 microns of thickness) of body base bottom surface.Laminate ply 222
It can also be made of the material with adhesive coating only on side, the side is the side contacted on the downside of microfluid base
Face.This layer can be made of the single coating band of the layer with adhesive 420, be manufactured by 3M.Exemplary band includes having production
The unilateral variant of Article Number 9783,9795 and the double-sided tape of 9795B, and can be obtained from 3M.Other acceptable layers can wrap
Include the band based on microcapsules based adhesive.
In use, box 200 is generally thermally connected with array of heat sources, the heat source is configured to the element (example of operation described device
Such as, valve, gate and processing region 210).In some embodiments, heat source is the behaviour by operating system
Make system and runs described device during use.Operating system includes processor (for example, computer), according to required regulation
It is configured to drive the heat source.The processor for being configured to operation microfluidic device is described for example, carrying on March 28th, 2001
The U.S. Application No. 09/819,105 gone out, application are incorporated herein by reference.
Table 1 outlines volume related with the multiple element of microfluid box, pump pressure and operating time.
Table 1
In some embodiments, microfluid box further includes recording element, ensures the box with single-orientated mutual
The diagnostic device of benefit receives, for example, receiving compartment in device.Recording element can be the letter at edge or corner from box
A series of single cut-out (as shown in fig. 38 a), or can be recesses, or need some unique being orientated placed in a device its
Its shape design.
In some embodiments, microfluid box includes two or more setting elements or benchmark, with thermal response material
It is used when material filling valve.Setting element can be located in base, usually on its top face.
Microfluid box can also be stackable, such as in order to be easy to store or transport, or can be configured to be loaded
Device receives, and as described further herein, multiple boxes is kept mutually close, but are not contacted.In order to realize this
Any one of two features, base may include two burrs, each along two opposite edges of the box each
Positioning, the burr configuration is on base upper surface.Thus, (ignore any record member in the case where box has rectangular characteristic
Part or mechanical keys), two burrs can be positioned along the long side of the box or along short side.
Valve
Valve is the microfluid element for usually having open state, allows material along channel from valve side
The channel in position (such as downstream of valve) passes through on position (for example, upstream of valve) to the valve other side.It is exemplary
Double valve be shown in Figure 40 A.Double valve tool is there are two channel, on the either side in a channel for adjusting its flowing at it,
However single valve only has there are one channel, configures on the side that it adjusts the channel of its flowing.
On startup, for example, by applying heat, valve is transformed into closed state, prevents material such as PCR- i.e.
Sample droplet along the channel from valve side to the other side from passing through.For example, valve includes one or more thermal response objects
Matter (TRS) is rolled into a ball, and is stablized relatively in the first temperature and is more mobility in second temperature.TRS group can be substantially
The agglomeration of solid group or smaller particle, collaboration is to hinder passing through on startup.The example of TRS include eutectic alloy (for example,
Solder flux), wax (for example, alkene), polymer, plastics, and combinations thereof.First and second temperature are not high enough to destroy material, all
Such as the polymeric layer for the microfluid box that valve is located therein.Usually, second temperature is less than about 90 DEG C and the first temperature is small
In second temperature (for example, about 70 DEG C or smaller).
For each group related with valve, room is communicated with described gas.In the one or more rooms of heating
Gas (for example, air) and by one or more TRS group be heated to second temperature when, indoor gas pressure will be corresponding
Group is moved in channel, and material is hindered to pass through along it.Other valves of network have identical structure and to be retouched with this paper
The same way for the valve stated is run.
In order to make valve seal be very firm and reliable, the flow channel of valve joint is made narrow
(150 μm wide and 150 μm are deep or narrower), and it is long so that the wax seals up that at least 0.5 or 1mm long is made in slype
Narrow passage, therefore reduce any leakage by the conduit wall.In the case of poor sealing, there are fluids in conduit wall week
Enclose the leakage by the wax.So flow channel is as narrow as possible, and is made longer, for example, up to~1mm.Valve
It is operated, the wax is pushed forward in this way, so that it is not returned by the air in the port that heating loads wax
To its original position.In this manner, air and wax are heated all during valve operation.
In various embodiments, Microfluidic networks may include that valve is bent as shown in Figure 40 B (as single valve
Door) to reduce the footprint of valve on box, and the cost of each section is therefore reduced for manufacturing high-densit microfluid base.
In the valve of Figure 40 B, the loading hole for TRS is at the center of the valve;The structure of any one end is entrance and goes out
Mouthful and shown only for illustrative purpose.Show single valve.
In various embodiments, the network may include bending valve as shown in figure 40 c, also be used as single valve
Door, to reduce the effective cross section of micro-valve door, can manufacture less expensive fine and close microfluidic device.
Floss hole
Drain discharge mouth (for example, floss hole in Figure 41) is to allow gas leaving channel while limiting (for example, preventing)
Liquid leaves the structure in the channel.Usually, drain discharge mouth includes one layer of porous hydrophobic material (for example, porous filter
Such as porous hydrophobic membrane from Osmonics), limit conduit wall.As discussed herein, drain discharge mouth can be used for by
Sample droplet is located in the required position in Microfluidic networks.
What the drain discharge mouth of the box was preferably formed by, it is maximized with will pass through the air capacity that they escape, together
When so that the channel volume under discharge discharge surface is minimized.It is preferred, therefore, that building floss hole so as in the case where discharging discharge surface
The shallow cross section of hydrophobic membrane and microchannel with high surface area.
Bubble removal drain discharge opening's edge channel generally and have at least about the length of 2.5mm (for example, at least about 5mm, until
Few about 7.5mm).The length of drain discharge mouth is typically at least about 5 double-lengths of channel depth within drain discharge mouth (for example, extremely
It is about 10 times, at least about 20 times few).For example, in some embodiments, the channel depth within drain discharge mouth is about 300
Micron or smaller (for example, about 250 microns or smaller, about 200 microns or smaller, about 150 microns or smaller).Bubble floss hole exists
It is optional in the Microfluidic networks of microfluid box described herein.
Channel depth within drain discharge mouth be usually drain discharge mouth upstream and downstream channel depth about 75% or
Smaller (for example, about 65% or smaller, about 60% or smaller).For example, in some embodiments, the channel in drain discharge mouth
Depth is that the channel depth of about 150 microns and drain discharge mouth upstream and downstream is about 250 microns.
Channel width within drain discharge mouth generally than the channel width of the upstream from floss hole and comes from floss hole
The channel width in downstream is at least wide by about 25% (for example, at least wide about 50%).For example, in exemplary embodiment, hydrophobic row
Put that the channel width in mouth is about 400 microns and the channel width from floss hole upstream and downstream is about 250 microns.
The embodiment of height multiplexing
Apparatus described herein and the embodiment of box can be constituted in this way, have high density microcosmic on single box
Fluid circuit, therefore this allows to handle multiple samples on single box parallelly or according to priority.Such multiple samples it is excellent
Select number include 36,40,48,50,64,72,80,96 and 100, but it is to be understood that also have other numbers be with it is herein
Device and box are consistent, wherein being considered convenient and practical.
Therefore, the channel of different configuration, sample inlet and related heater network are it is contemplated that it can promote
The sample of the number is handled on single box, this is in invention scope of the present disclosure within.Similarly, more with such height
The alternative detector configurations that are used in combination of box of road modulation are also within the scope of description herein.
In exemplary embodiment, the box of height multiplexing has 48 channels PCR, and with each in channel
The independent control of a valve, each channel have 2 groups of thennocycling protocols, as shown in figure 43.It is described in the embodiment of Figure 43
Heater array is at three arrays.Heater in two independent glassy zones only applies heat to the micro flow in each channel
Valve in volume grid.Due to the low-thermal conductivity of glass, the independent valve can heat independently of each other.This allows sample
It is loaded into different times in the box, and is transmitted to PCR reative cells independently of each other.PCR heaters are mounted on silicon substrate
On layer ,-and be independently not easy to be heated, but therefore allow the batch processing of PCR samples, wherein from different channels
Multiple samples are expanded by identical group of heating/cooling cycle.2 groups of (left side and right sides preferably are arranged in for PCR heaters
The not mutual telecommunication of heater arrays on side) in, therefore allow individual sample degree of control.
Figure 42 shows typical box, discloses the inlet configuration of 48- sample boxes.Inlet configuration with with 9mm spacing position
The automatic liquid relief machine of dispensing head be compatible.For example, such machine with 4 heads can be one in 12 dispersion steps
4 entrances of secondary loading are used for the box of Figure 42.
Figure 44 shows, closely, the exemplary spacing of valve and channel in the adjacent channel of Multi-example microfluid box.
Figure 45 and 46 respectively shows the heater arrays of the exemplary box shown in Figure 44 and the closure (close of entrance
up)。
Figure 47 A-47C show multiple views of the embodiment of the box of the height multiplexing of radial configuration, have
Entrance, microfluidic channels and the PCR reaction zones of certain amount.
The multiple embodiments shown in Figure 42-47C and the liquid configured different from particular examples described herein
Distributor, it is compatible to receive compartment and detector.
In another preferred embodiment (not showing in figure), box and device are configured so that, not so as to read head
Sample inlet is covered, therefore allows to load independent sample, while other samples undergo PCR thermal cycles.
Ensure the heater configuration for being evenly heated region
The other side of apparatus described herein is related to the method for the region heating of equal control Microfluidic networks
And device, the Microfluidic networks include but is not limited to one or more microfluid elements.In exemplary embodiment
In, multiple heaters can be configured to while and be evenly heated the region of the microfluid box, such as PCR conversion zones.
In preferred embodiments, include the micro flow with Microfluidic networks of one or more microfluid elements
Body box is contacted with the heat source within the device of configuration is suitble to.Heat source is configured in this way, to position specific heating unit
Part is to heat the specific element of the Microfluidic networks of the box.
Figure 48 shows the viewgraph of cross-section of exemplary microfluid box, to show when the box is placed in instrument, PCR
Relative position of the channel relative to heater.The local equal proportion that view in Figure 48 is also referred to as the box being located in heater chip regards
Figure.The display of window 903 on the channels PCR in the box is in the perspective.The channels PCR 901 are (for example, 150 μ μ deeply × 700
It is wide), it is shown in the upper layer of the box.The laminate ply 905 (for example, 125 μ are thick) of the box directly the channels PCR 901 with
Under.Another layer (for example, 125 μ are thick) of hot interface laminated material 907 on the box is located immediately at 905 or less laminate ply.
Heater is located in hot interface laminated material another layer 913 below.Heater is lithographic definition and the metal layer of etching
(generally about for goldIt is thick).TiW layers be deposited on the top and bottom of layer gold as adhesive layer.The base used
Layer is glass, fused silica or quartz wafer, the thickness with 0.4mm, 0.5mm or 0.7mm or 1mm.2 μm of silica it is thin
Electric insulation layer is upper at the top of metal layer to be used as insulating layer.In addition the parylene of such as 2-4 μm of thin electric insulation layer
On can also being deposited at the top of silicon oxide surface.Also show two long heaters 909 and 911, as described further herein.
About Figure 49 A and 49B, PCR conversion zones 1001 generally have the volume of~1.6 μ l, configured with long side and short
Side, respective associated heating element.Therefore described device preferably includes configured along the side of PCR conversion zones four
A heater, and be configured to heat the PCR conversion zones, as shown in the exemplary embodiment of Figure 38 A:Long top
Heater 1005, long bottom heater 1003, short left heater 1007 and short right heater 1009.Long top adds
Small―gap suture between hot device 1005 and long bottom heater 1003 generates insignificant temperature gradient (along PCR reaction zones
It is less than 1 DEG C on the width in the channels PCR of any point of length of field), therefore generate effectively uniform temperature in whole PCR conversion zones
Degree.Heater in the short edge of PCR reactors provides heat to offset the slave reactor center generated by two long heater
To the gradient at reactor edge.It should be understood by one skilled in the art that around the one or more of PCR conversion zones positioning
Other constructions of heater are consistent with methods and apparatus described herein.For example, " length " side of conversion zone can configure
It is heated at by two or more heaters.By the specific orientation of heater and it is configured to even conductive with undesirable heat
Homogeneous heating region is generated in base, this is because glass or the bad heat conductivity of quartz or fused silica base are for helping
Help the independent operation of the independent operation and multiple channels PCR of multiple microfluid element such as valves.
In preferred embodiments, each heater has relevant temperature sensor.In the embodiment of Figure 49 A,
Single temperature sensor 1011 is used for two long heaters.Also show the temperature sensor for short left heater
1013, it is used for the temperature sensor 1015 of short right heater.The temperature sensor in reactor center for provide feedback and
Control is supplied to the magnitude of power of two long heaters, however each short heater has the special temperature for being adjacent to its placement
Sensor is spent to control it.As described further herein, when heater is without receiving to cause the electric current of their heating,
At this moment, temperature sensor is preferably arranged in the information for being adjacent to the processor transmission about temperature.This can be followed with electric current
The suitable control of ring is realized.
In order to reduce the number of sensor or heating element needed for control PCR heaters, the present inventor can use
Therefore heater need not have the independent sensor special for each heater to sense and heat.Another
In a embodiment, each of four heaters can be designed to there is wattage appropriate, and by four heater strings
Join or be connected in parallel so that the number of electrically controllable element is reduced to only 1 from 4, therefore reduces the burden on electronic instrument.
Figure 49 B show the enlarged view of the heater and temperature sensor that are used in combination with the PCR conversion zones of Figure 49 A.
Temperature sensor 1001 and 1013 is designed to that with room temperature resistance be about 200-300 ohm.This resistance value is under
Row measure, control the metal layer of deposition thickness (for example,Interlayer), and
And the metal wire of etching winding is with the length of width and 20-40mm with about 10-25 μm.It is given using metal in this layer
It is about 0.5-20 DEG C/ohm of rank to give its temperature coefficient of resistivity, preferably within the scope of 1.5-3 DEG C/ohm.It is surveyed in higher temperature
Amount resistance will can measure the accurate temperature of these sensing stations.
It can be used for multichannel PCR for uniformly heated construction for what single PCR conversion zones were shown in Figure 49 A
Box, wherein multiple independent PCR reactions occur.
Each heater can be by the processor and/or control circuit that are used in combination with apparatus described herein independently
Control.Figure 50 display thermal images, the top surface of the microfluid box with heater configured from such as Figure 49 A and 49B, often at this time
A heater is activated successively, as follows:(A) only long top;(B) only long bottom;(C) only short left side;(D) the only short right side
Side;(E) all four heaters are opened.Version (F) display with Figure 50 in other image version same ratios conversion zone and plus
The view of hot device.Temperature strip is also shown in figure.
The use of (cutaway) in box base is cut to improve the cooling rate during PCR cycle
During the PCR amplification of nucleotide sample, the thermal cycle of certain amount is carried out.In order to improve efficiency, each heat
Cooling between application is preferably as far as possible rapidly.The cooling rate of raising can use a variety of variants of heating base to realize,
As shown in Figure 51 A-51C.
Realize that a kind of method being quickly cooled down is to cut the part of microfluid box base, as shown in Figure 51 A.Figure 51 A
Adjustment of the printing plate be along the cross section of dotted line A-A ' the exemplary microfluid boxes taken, as Figure 51 A lower version on mark.It shows
PCR conversion zones 901, and typical heater 1003.Also show two cut portions, one of label 1201,
Positioning beside heater, the heater along PCR conversion zones long side positioning.Cut portion such as 1201 reduces the heat of box
Quality, and also allow for air and recycled in cut portion.The two aspect allow heat rapidly from PCR conversion zones immediately
Near conduct.Other cut portion constructions, it is consistent with this technology such as in shape, position and number.
Realize that another mode being quickly cooled down is the cut portion of heater base, as shown in Figure 51 B.Under Figure 51 B
Version be along the cross section of dotted line A-A ' exemplary the microfluid boxes and heater base taken, as Figure 51 B adjustment of the printing plate on mark
Note.Show PCR conversion zones 901, and typical heater 1003.Four cut portions are also shown, one of label
1205, positioned beside heater, the heater along PCR conversion zones long side positioning.Cut portion such as 1205
The thermal mass of heater base is reduced, and also allows for air and is recycled in cut portion.The two aspects allow heat rapid
From PCR conversion zones immediately near conduct.Four individual cut portions be shown in Figure 51 B so as not to destroy for
The control circuit of multiple heaters.Other cut portion constructions, such as in shape, position and number, with the technology of the present invention phase
Hold.These cut portions can be by generating selected from following method:Use the selective etch of Wet-type etching method, deep reaction
Property ion(ic) etching, uses CO2The selective etch (preventing the stress near skin breakage or surface) of laser or nanosecond laser,
Selective machine drilling, selective ultrasonic drilling, or selective abrasive grain sandblasting (abrasive particle blasting).
The mechanical integrity of heater must be carefully kept, while reduce material as much as possible.
Figure 51 C display cuttings are cold during the cooling stage to increase thermal cycle with the air cooled combination of use environment
But rate.A large amount of cooling is occurred by the convection losses from the bottom surface of heater surfaces to surrounding air.The convection current is damaged
The driving force of mistake is the temperature difference between glass surface and air themperature.Environment is reduced by using such as peltier cooler
Air themperature can increase cooling rate.Convection heat losses can also be increased by being maintained at air higher than zero speed.
It is for 1 seconds until 92 DEG C, and there for setting heating, 62 DEG C are then cooled to, and kept for 10 seconds
The example of scheme, the thermal circulation performance obtained by construction described herein is shown in Figure 52.Circulation time is about 29 seconds, from
62 DEG C are heated and are stablized and at 92 DEG C need 8 seconds, and cooling from 92 DEG C and stable need 10 seconds at 62 DEG C.
The manufacturing method of box
Figure 53 shows the flow chart 2800 of the assembling process of exemplary box as described further herein.This field is common
It will be appreciated by the skilled person that multiple steps can be any given to be carried out different from the sequence stated in Figure 53, and additionally
The step of can be carried out by the alternative approach stated in the figure.It will also be understood that wherein for carrying out two or more work(
It can illustrate independent step, such function, which can synchronize, to be carried out and be combined in single step, and is retouched with this paper
The overall process stated is consistent.
2802, laminate ply is administered to microfluid base, the microfluid base is transformed in advance
At with the Microfluidic networks wherein built;Edge is modified from laminated material, and wherein they overflow the boundary of base.
2804, wax is distributed and in the micro-valve door of Microfluidic networks that is loaded into microfluid base.Herein
It further describes and carries out this exemplary process.
2806, the box is checked to ensure that the wax from step 2804 correctly loads, and comes from step 2802
Laminated material be correctly joined to microfluid base.If base is unsatisfactory for any one or two of these tests, by it
It excludes.If not up to any one of these tests or both reexamines wax point according to what is applied repeatedly for base
Match or laminated material step of applying.
2808, drain discharge membrana oralis is administered to, and is thermally bonded to, at the top of the microfluid base on wax valve,
On the opposite face of the base from laminated material.Film edge more than base boundary has been modified.
2810, inspection component is micro- without thermal chokes to ensure that drain discharge membrana oralis is fully attached to microfluid base
See fluid channel.If any one channel is obstruction, or if the combination between film and base is not good enough, excludes described group
Part, also, in the case of exclusion event repeatedly, reexamine above-mentioned processing step.
2812, heat transfer bed course is applied to the bottom laminated material of the box.
2814, two slugs are administered to the top of microfluid base, a covering valve, and second guarantor
Shield discharge membrana oralis.It should be appreciated that single labelled item can be designed to realize the two effects.
2816, label in addition is printed or application is to show that identification feature, the bar code number on such as described box are criticized
Number and term of validity.It is preferred that the surface that the one or more of these labels has space and can write, allows user to use
Hand generates identification annotation on this mark.
2818, in order to promote to transport and be transported to consumer, assembly and label box is the stacking and packet of grouping
Mounted box, such as 25 one group or 10 one group or 20 one group or 50 one group.Preferably, the packaging is via inertia
And/or no moisture medium.
Exemplary wax deposit method
Deposition of the wax in Microfluidic networks valve can use the example shown in Figure 54 A and 54B such as in step 2804
The equipment of act property carries out.DispenseJet series DJ-9000 (Figure 54 A and 54B) be for multiple fluid provide high speed delivery and
The non-contact dispenser of superior fixing fabric structure, including surface fixed adhesive, underfilling, sealant, conformal coating, UV are viscous
Mixture and silver epoxy.DJ-9000 is sprayed in confined space for small to 200 microns and in point of base's such as punch die
Width (fillet wet-out widths) is soaked with the small fillet to 300 microns is generated on side.Fluid is assigned as discrete by it
Point or quickly continuous point are to form the fluid stream of 100- microns of (4mil) diameters from nozzle.It with it is other commercially available
System is fully compatible, such as Asymtek Century C-718/C-720, Millennium M-2000 and Axiom X-
1000 serial distribution systems.
DJ-9000 is manufactured by Asymtek under Manufacture quality control standard, it is therefore an objective to be provided accurate and reliable
Performance.The ideal format of described device is as follows.
* with maximum circulation rate
The sectional view of the device is shown in Figure 54 B.
The theory of operation of DJ-9000
DJ-9000 have it is normally closed, air starting, spring return mechanism, using momentum transfer principle to arrange
Go out the material of accurate volume.Compressed air be by high-speed solenoid adjust with from pedestal withdraw needle assemblies.It is charged to fluid chamber
In fluid flow on the base.When air empties, needle is quickly propelled to closed position, and fluid is passed through pedestal and spray
Mouth is replaced as drops.When with distributor automation movement combination, multiple droplets of sequential transmissions can be used to form compared with
Big dispensed volume and pipeline.
The equipment has multiple adjustable features:Following features influence the performance of DJ-9000 and are generally adjusted into
Meet specific treatment conditions.
Fluid pressure should be set in this way, so that fluid is filled into the pedestal, but should not be pushed through by fluid
It is affected in pedestal and nozzle.In general, higher Fluid pressure causes to spray higher volume of material.
Stroke adjusts the displacement distance of (stroke adjustment) control needle assemblies.The control is to rotate counterclockwise
, to increase needle assemblies movement, or rotate clockwise to reduce movement.The increase of displacement distance will frequently result in injection more substantially
Long-pending material.
Solenoid valve control valve operates.When energized, it allow spray air chamber in air compressed spring and
Therefore needle assemblies are improved.When switching off the current, it discharges air and spring forces piston downwards so that the needle point contacts pedestal.
Pedestal and nozzle geometry are usually the principal element for controlling distribution material volume.Based on application and fluid properties
Measure pedestal and jet size.Other parameters are adjusted according to pedestal and nozzle selection.Obtainable pedestal and jet size are under
It is listed in literary table.
Thermal control component:Fluid temperature (F.T.) often influences fluid viscosity and flow behavior.DJ-9000, which is equipped with, ensures steady flow
The thermal control component of temperature.
Points And lines parameter:In addition to DJ-9000 hardware constructions and setting, Points And lines parameter is set in software program
(being known as FmNT) is with the size and quality of the Points And lines of control distribution.
Wax is loaded in valve
Figure 55 A and 55B show that distribution enters in the micro-channel device of the heating with just size and geometry
How cerotin is for being really loaded into the microchannel of microfluid box to form valve by the combination of controlled heat drop.Heating distributer
Head can be accurately located on the ingate of the microchannel in microfluidic device, and can be arrived with small with 20% accuracy
The wax drop of 75 nanoliters of capacity distribution fusing.The ingate of micro-channel device is sized in such a way, use example
It, can be by the bottom of the drop accurate delivery of 75nl to ingate such as compressed air, or in a manner of similar to ink jet printing method
Portion.Micro-channel device is maintained to the temperature of wax fusing point or more, therefore allows wax to be maintained at fusing shape immediately after dispensing wax
State.After drop falls on ingate bottom, the wax of fusing is pumped by capillarity in narrow channel.The volume of narrow part
It is designed to be approximately equal to the maximum typical amount being assigned in ingate.
Heater multiplexing (under software control)
The other side of apparatus described herein is related to the method in system and its element internal control heating capacity, such as
It is illustrated in Figure 56.The method generates the energy efficiency of the bigger of apparatus described herein, because whole heaters are not
Heating simultaneously, and given heater only receives electric current in portion of time.
Usually, the heating of microfluid element, such as PCR conversion zones are appropriately configured by making electric current pass through
The heater control of micro Process (microfabricate).It can be by periodically being switched with a variety of pulse widths modulation (PWM)
Electric current further controls heating, and wherein pulse width modulation refers to the ratio of opening time/shut-in time of electric current.It can be with
Electric current is supplied by micro-machined heater is connected to high voltage source (for example, 30V), this can be controlled with pwm signal.
In some embodiments, described device includes 48 PWM signal generators.The operation of PWM generator includes generating to have selection
Programming cycle (end counting) and gap periods signal.For example, signal can be the 4000 μ s for having 1us gap periods
(microsecond), in said case, PWM generator can be provided in zero beginning and carried out with 1 μ s increments until it reaches 4000 μ
It returns to zero counter when s.Thus, the calorie value of generation can be adjusted by adjusting end and counting.High end counts
Corresponding to the time span of bigger, micro-machined heater receives electric current and therefore generates a greater amount of heats therebetween.
In various embodiments, in addition to above-mentioned end counts and gap periods, the operation of PWM generator can also wrap
Include programmable initial count.In such embodiments, multiple PWM generators can generate signal, and the signal can be with
It is selectivity non-overlapping (for example, by on-time of the multiple heaters of multiplexing), so that being no more than high voltage
The current capacity of power supply.It can be multiple with different PWM signal generator control in the case where changing starting and end is counted
Heater.Heater can be divided into group (banks), and one of group (bank) limits the heating of one group of identical initial count
Device.For example, 36 PWM generators can be grouped as six different groups, each group is (right corresponding to certain part of PWM cycle
In the example be 500ms).The end counting of each PWM generator can be programmed selectively will so as not to be more than six heaters
It opens at any given time.A part for PWM cycle can be selected as to the dead time (to be counted the example and 3000 arrives
4000), there is no heating therebetween and smart temperature sensing circuit can sense the temperature using the time.Following table table
Show the PWM cycle of examples detailed above:
Initial count end counts maximum end and counts
Group 1
Group 2
Group 3
Group 4
Group 5
Group 6
Using detecting system to measure/detect the fluid in the rooms PCR
Described device optionally has very sensitive fluorescence detector, can be collected from the rooms PCR 210 of microfluid box
Fluorescence.The detector is used to detect the presence of liquid in the room, decides whether a kind of measurement for carrying out PCR cycle.With liquid
Body takes background reading before filling the room.Another reading is taken after microfluid operation has carried out, this should cause
With the rooms liquid filling PCR.The presence of liquid changes the fluorescence reading from the room.The calculation that programmable threshold value is used to program
Method is adjusted in processor (for example, the second reading must be over the first reading 20%).The side of journey if two readings are not on the permanent staff
It is different other than boundary, then it is assumed that liquid does not enter into the room, and PCR cycle does not start the room.Instead, it will alert
It is issued to user.
Computer program product
In various embodiments, include for operating described device for the computer program product used in device herein
Computer-readable instruction on it.
In various embodiments, computer program product may include causing system to carry out following one or more to refer to
It enables:Export the instruction that the microfluid box is placed in compartment;Read sample label or microfluid box label;For using
Person exports instruction with input sample identifier;Instruction is exported for user and transmits member to load sample with sample with PCR-
Part;Instruction is exported so that PCR- to be introduced into sample in microfluid box for user;For user export instruction with
Microfluid box is placed on and is received in compartment;Instruction is exported to close lid with running force element for user;For making
User exports instruction so that PCR- is used sample with sample by the way that the air of about 0.5mL to about 5mL volumes is injected PCR-
Pressurization is in microfluid box;With the sample state of a process information in one or more channels of the output from the box.
In various embodiments, computer program product may include causing system to carry out following one or more to refer to
It enables:Heating PCR uses sample under the thermal cycle conditions for generating PCR amplification suitable for the polynucleotides of the sum in;By neutralization
Polynucleotides sample or its PCR amplification be that selective at least one probe contacts for polynucleotide sequence;It will neutralize
Polynucleotides sample and each of negative control polynucleotides independently connect under thermal cycle conditions with PCR reagent mixture
It touches, the thermal cycle conditions are suitable for PCR amplification and negative control polynucleotides of the independent polynucleotides sample for generating and neutralizing
PCR amplification son;By the polynucleotides sample of neutralization or its PCR amplification and negative control polynucleotides or its PCR amplification
Be that selective at least one probe contacts for polynucleotide sequence;Output polynucleotide sequence is present in biological sample
Measurement, the polynucleotide sequence correspond to the probe, condition be the sum in polynucleotides sample or its PCR amplification son
The middle detection probe;And/or if in negative control polynucleotides or its PCR amplification detection probe, export pollution
As a result measurement.
In various embodiments, computer program product may include that system is caused to carry out one of the method automatically
Or one or more instructions of multiple steps.
In multiple embodiments, microfluid box includes two or more sample channels, includes respectively sample inlet valve,
Bubble removal floss hole, the pump of thermal starting, the valve and PCR conversion zones of thermal starting, wherein it is computer-readable instruction by with
One or more elements in each channel in independent operating system are set to, independently of each other, and for making detector survey
Measure the fluorescence from PCR reaction zones.
Sample
In various embodiments, sample may include PCR reagent mixture comprising polymerase and a variety of nucleotide.
PCR reagent mixture can be the form of one or more freeze-drying beads, and prepare PCR- and can be wrapped with the step of sample
It includes and contacts PCR beads to generate PCR reagent mixture solution with liquid.In yet another embodiment, each channel PCR
There can be the drying of preloaded or freeze-drying ASR reagents, so that user only needs the polynucleotides sample that will be prepared defeated
Enter into PCR.In another embodiment, the channels PCR can only have application specific measure in advance and preloaded
Probe and primer, and user inputs the sample that is mixed with PCR reagent.
In various embodiments, can be configured to will be from external heat source under thermal cycle conditions for Microfluidic networks
It is thermally coupled to the sample mixture of the polynucleotides sample including PCR reagent and neutralization, the thermal cycle conditions are suitable for from neutralization
Polynucleotides sample generate PCR amplification son.
In various embodiments, PCR may further include positive control plasmid with sample and for the plasmid
At least part be selective fluorogenic hybridization probe.In various embodiments, PCR- further includes that sample is slow with sample
Fliud flushing, and be selective at least one probe for polynucleotide sequence, for example, as the disease selected from consisting of the following group
The polynucleotide sequence of the feature of substance:Gram-positive bacterium, gramnegative bacterium, yeast, fungi, protozoan, and
Virus.
In various embodiments, microfluid box can accommodate negative control polynucleotides, wherein Microfluidic networks
Can be configured in and polynucleotides sample and negative control polynucleotides each on PCR reagent mixture in heat
PCR is independently carried out under cycling condition, the thermal cycle conditions are suitable for PCR amplification of the independent polynucleotides sample for generating and neutralizing
With PCR amplification of negative control polynucleotides.Each channel of multichannel box as described herein can execute two instead
It answers, due to the presence of two fluorescence detecting systems in each channel.A variety of reaction combinations can be carried out in box, such as one logical
Two example reactions in road, positive control and negative control in two other channels;Or the example reaction in a channel and
A negative control in internal contrast and an individual passage.
In various embodiments, it is selective at least one probe that sample, which may include for polynucleotide sequence,
It includes the polynucleotides sample that will be neutralized or its PCR amplification and the spy with the step of sample wherein to prepare PCR- by it
Needle contacts.The probe can be fluorogenic hybridization probe.Fluorogenic hybridization probe may include be connected to fluoreporter dyestuff and
The polynucleotide sequence of fluorescent quenching dyestuff.PCR reagent mixture can also be including positive control plasmid and for the plasmid
At least part be selective plasmid encoding luciferase hybridization probe, and the microfluid box can be configured to allow fluorescence miscellaneous
Hand over the detection of the Individual optical of probe and plasmid encoding luciferase hybridization probe.
In various embodiments, the probe can be selectivity for the polynucleotide sequence as biological characteristic
, for example, by using DNA or any biology of ribonucleic acid polynucleotides.Thus, the probe is for any biology
Can be selective.Suitable biology includes mammal (including mankind), birds, reptiles, amphibian, and fish is raised and train
Animal, wild animal, the biology of extinction, bacterium, fungi, virus, plant, etc..The probe can also be for using them certainly
The biological components of body polynucleotides are selective, such as mitochondrias.In some embodiments, probe is choosing for microorganism
Selecting property, for example, used in food production biology (for example, the yeast used in fermented product, the mould that is used in cheese or
Bacterium, etc.) or pathogen (for example, the mankind, raise and train or wild mammal, raises and train or wild birds, etc.).At some
In embodiment, probe is for being selective selected from consisting of the following group of biology:Gram-positive bacterium, gram-negative
Property bacterium, yeast, fungi, protozoan, and virus.
In various embodiments, probe is that optionally, the polynucleotide sequence is for polynucleotide sequence
Selected from the feature by following group of groups of biology:Staphylococcus species (Staphylococcus spp.), for example, epidermis Portugal
Grape coccus (S.epidermidis), staphylococcus aureus (S.aureus), methicillin resistant S staphylococcus resist
Vancomycin staphylococcus (Vancomycin-resistant Staphylococcus);Streptococcus (Streptococcus)
(for example, α, β or γ-haemolysis, A, B, C, D or G groups) such as streptococcus pyogenes (S.pyogenes), Streptococcusagalactiae
(S.agalactiae);Enterococcus faecalis (E.faecalis), Enterococcus durans (E.durans) and enterococcus faecium
(E.faecium) (it was streptococcus fecalis (S.faecalis), streptococcus durans (S.durans), streptococcus faecalis in the past
(S.faecium));Non-enterococcus D group of streptococcus, for example, Streptococcus suis (S.bovis) and streptococcus equi (S.equines);Grass
Viridans streptococci (Streptococci viridans), for example, Streptococcus mutans (S.mutans), Streptococcus sanguis
(S.sanguis), streptococcus salivarius (S.salivarius), streptococcus mitis (S.mitior), A.milleri, group of stars hammer
Bacterium (S.constellatus), intermediate streptococcus (S.intermedius) and streptococcus anginosus (S.anginosus);Dolphin
Streptococcus (S.iniae);Streptococcus pneumonia (S.pneumoniae);Eisseria (Neisseria), for example, meningitis
Neisser's coccus (N.meningitides), Diplococcus gonorrhoeae (N.gonorrhoeae), saprophytic Neisseria species
(saprophytic Neisseria sp);Erysipelothrix (Erysipelothrix), for example, erysipelothrix rhusiopathiae
(E.rhusiopathiae);Listeria spp species (Listeria spp.), for example, Listeria Monocytogenes
(L.monocytogenes), rarely Yi Shi listeria spps (L.ivanovii) and Si Shi listeria spps
(L.seeligeri);Bacillus (Bacillus), for example, Bacillus anthracis (B.anthracis), waxy gemma bar
Bacterium (B.cereus), bacillus subtilis (B.subtilis), black bacillus subtilis (B.subtilus niger), Su Yun
Golden bacillus (B.thuringiensis);Nocardia asteroide (Nocardia asteroids);Legionnella
(Legionella), for example, legionella pneumophilia (L.pneumonophilia), pneumocystis (Pneumocystis), for example, card
Family name's lung sac worm (P.carinii);Enterobacteriaceae (Enterobacteriaceae) such as Salmonella (Salmonella), will
Hayes Pseudomonas (Shigella), Escherichia (Escherichia) is (for example, Escherichia coli (E.coli), Escherichia coli
O157:H7 strains;Klebsiella (Klebsiella), enterobacteria (Enterobacter), Serratieae (Serratia) become
Shape Pseudomonas (Proteus), morganella morganii category (Morganella), Providencia (Providencia), Yersinia ruckeri
Belong to (Yersinia), etc., for example, Salmonella (Salmonella), for example, salmonella typhi (S.typhi) A type
Salmonella paratyphi (S.paratyphi A), moscow' paratyphi B (B) (Xue Shi salmonellas
(S.schottmuelleri)) and moscow' paratyphi C (Bacterium paratyphosum C (S.hirschfeldii)), Dublin
Salmonella (S.dublin) Salmonella choleraesuls (S.choleraesuis), Bacterium enteritidis (S.enteritidis),
Salmonella typhimurium (S.typhimurium), salmonella heidelberg (S.heidelberg), Salmonella newport
(S.newport), salmonella infantis (S.infantis), Agora salmonella (S.agona), Meng get Wei salmonellas
(S.montevideo) and salmonella saint paul (S.saint-paul);Shigella (Shigella) is for example, subgroup:A,
B, C and D, such as shigella flexneri (S.flexneri), bacillus ceylonensis A (S.sonnei), Shigella bogdii
(S.boydii), shigella dysenteriae (S.dysenteriae);Mycetozoan (Proteus) (proteus mirabilis
(P.mirabilis), mycetozoan (P.myxofaciens) is glued in proteus vulgaris (P.vulgaris), and production), morganella morganii category
(Morganella) (morganella morganii strain (M.morganii));Providencia (Providencia) (Lei Shi Pu Luowei
Step on this bacterium (P.rettgeri), production alkali Providence (P.alcalifaciens) and providencia stuartii
(P.stuartii));Yersinia ruckeri (Yersinia), for example, Yersinia pestis (Y.pestis), enterocolitis
Ademilson Salmonella (Y.enterocolitica);Hemophilus (Haemophilus), for example, haemophilus influenzae
(H.influenzae), haemophilus parainfluenzae (H.parainfluenzae) haemophilus aphrophilus (H.aphrophilus),
Haemophilus ducreyi (H.ducreyi);Brucella (Brucella), for example, miscarriage type brucella
(B.abortus), alcaligenes melitensis (B.melitensis), Brucella suis (B.suis), dog brucella
(B.canis);Francisella (Francisella), for example, soil draws hot Francisella (F.tularensis);It is false
Zygosaccharomyces (Pseudomonas), for example, pseudomonas aeruginosa (P.aeruginosa), Pseudomonas paucimobilis
(P.paucimobilis), it is false single to eat acid for pseudomonas putida (P.putida), Pseudomonas fluorescens (P.fluorescens)
Born of the same parents bacterium (P.acidovorans), Burkholderia pseudomallei (pseudomonad) (Burkholderia
Pseudomallei), Burkholderia mallei (Burkholderia mallei), Burkholderia
(Burkholderia cepacia) and germ oligotrophy unit cell (Stenotrophomonas maltophilia);Bent stick
Pseudomonas (Campylobacter), for example, campylobacter fetus (C.fetus fetus), campylobacter jejuni (C.jejuni),
Campylobacter pylori (C.pylori) (helicobacter pylori (Helicobacter pylori));Vibrio (Vibrio), for example,
Comma bacillus (V.cholerae), vibrio parahaemolytious (V.parahaemolyticus), vibrio mimicus (V.mimicus), molten algae
Vibrios (V.alginolyticus), vibrio hollisae (V.hollisae), Vibrio vulnificus (V.vulnificus) and non-agglutination arc
Bacterium (nonagglutinable vibrios);Fusobacterium (Clostridia), for example, C.perfringens
(C.perfringens), clostridium tetani (C.tetani), clostridium difficile (C.difficile), clostridium botulinum
(C.botulinum);Actinobacillus (Actinomyces) is for example, Yi Shi Actinobacillus (A.israelii);Bacteroides
(Bacteroides), for example, bacteroides fragilis (B.fragilis), bacteroides thetaiotaomicron (B.thetaiotaomicron), Ji Shi
Bacteroid (B.distasonis), bacteroides vulgatus (B.vulgatus), bacteroides ovatus (B.ovatus), excrement bacteroid
(B.caccae) and Bacteroides merdae (B.merdae);General Salmonella (Prevotella), for example, prevotella melanogenicus
(P.melaninogenica);Fusobacterium (genus Fusobacterium);Treponema (Treponema), for example, it is grey
White treponema place subspecies (T.pallidum subspecies endemicum), the thin and delicate subspecies of Spirochaeta pallida
(T.pallidum subspecies pertenue), spot disease treponema (T.carateum) and Spirochaeta pallida are grey
White subspecies (T.pallidum subspecies pallidum);Borrelia (genus Borrelia), for example, cloth
Borrelia burgdorferi (B burgdorferi);Leptospira (genus Leptospira);Streptobacillus
(Streptobacillus), for example, Streptobacillus moniliformis (S.moniliformis);Spirillum (Spirillum), for example, small
Spirillum (S.minus);Mycobacterium (Mycobacterium), for example, mycobacterium tuberculosis (M.tuberculosis), ox
Mycobacteria (M.bovis), mycobacterium africanum (M.afficanum), mycobacterium avium (M.avium), Mycobacterium intracellulare
(M.intracellulare), mycobacterium kansasii (M..kansasii), mycobacterium xenopi (M.xenopi), extra large branch
Bacillus (M.marinum), mycobacterium buruli (M.ulcerans), mycobacterium fortutitum compound (M.fortuitum
Complex) (mycobacterium fortutitum and Mycobacterium chelonei (M.chelonei)), Mycobacterium leprae (M.leprae), Asia point
Branch bacillus (M.asiaticum), Mycobacterium chelonei abscess subspecies (M.chelonei subsp.Abscessus), false branching bacillus
(M.fallax), mycobacterium fortutitum (M.fortuitum), Ma Ermo mycobacteria (M.malmoense), lower Chu Shi branch bars
Bacterium (M.shimoidei), mycobacterium habana (M.simiae), Si Shi mycobacterias (M.szulgai), mycobacterium littorale
(M.xenopi);Mycoplasmas (Mycoplasma), for example, human-type mycoplasma (M.hominis), oral cavity mycoplasmas (M.orale),
Saliva mycoplasmas (M.salivarium), fermentation mycoplasmas (M.fermentans), Mycoplasma pneumoniae (M.pneumoniae), ox
Mycoplasmas (M.bovis), tuberculosis mycoplasmas (M.tuberculosis), fowl mycoplasmas (M.avium), leprosy mycoplasmas
(M.leprae);Mycoplasmas (Mycoplasma) belongs to, for example, genital tract mycoplasmas (M.genitalium);Urea mycoplasmas
(Ureaplasma), for example, solution urea mycoplasmas (U.urealyticum);Trichomonas (Trichomonas), for example, vagina hair
Trichomonad (T.vaginalis);Cryptococcus (Cryptococcus), for example, Cryptococcus neoformans (C.neoformans);Organize born of the same parents
Pseudomonas (Histoplasma) is starched, for example, Histoplasma capsulatum (H.capsulatum);Candida (Candida), example
Such as, Candida albicans (C.albicans);Aspergillus sp (Aspergillus sp);Coccidioides immitis
(Coccidioides), for example, posadasis spheriforme (C.immitis);Blastomyces (Blastomyces), such as the life of dermatitis bud
Bacterium (B.dermatitidis);Coccidioides immitis (Paracoccidioides), for example, Paracoccidioides brasiliensis
(P.brasiliensis);Penicillium (Penicillium), for example, penicillium Marneffei (P.marneffei);Fibrillae of spores
Bacterium (Sporothrix), for example, Sporothrix schenckii (S.schenckii);Rhizopus (Rhizopus), Rhizomucor
(Rhizomucor), absidia (Absidia) and Basidiobolus (Basidiobolus);By Bipolaris
(Bipolaris), branch spore mould (Cladophialophora), Cladosporium (Cladosporium), Drechslera
(Drechslera), Exophiala (Exophiala), Fonsecaea (Fonsecaea), Phialophora
(Phialophora), Xylohypha (Xylohypha), Ochroconis (Ochroconis), beak branch spore are mould
(Rhinocladiella), disease caused by Scolecobasidium (Scolecobasidium) and Wangiella (Wangiella)
Disease;Trichosporon cutaneum (Trichosporon), such as Fructus Atriplicis Sibiricae trichosporon cutaneum (T.beigelii);Bud gives birth to schizomycete
(Blastoschizomyces), for example, head bud life schizomycete (B.capitatus);Plasmodium (Plasmodium), for example,
Plasmodium falciparum (P.falciparum), Plasmodium vivax (P.vivax), egg type plasmodium (P.ovale) and malariae
(P.malariae);Babesia species (Babesia sp);Trypanosomonas protozoan (protozoa of the genus
Trypanosoma), for example, schizotrypanum cruzi (T.cruzi);Leishmania (Leishmania), for example, Leishmania donovani
(L.donovani), leishmania major (L.major) crithidia cunninghami (L.tropica), Mexico Li Shiman are former
Worm (L.mexicana), leishmania brasiliensis (L.braziliensis), leishmania brasiliensis (L.viannia
braziliensis);Toxoplasma (Toxoplasma), for example, Earth's bow shock (T.gondii);Na Geli belongs to (Naegleria)
Or the amoeba of Acanthamoeba (Acanthamoeba);Histolytica Nei A meter (Entamoeba histolytica);Lan Shi goes into business
Flagellate (Giardia lamblia);Cryptosporidium (genus Cryptosporidium), for example, Cryptosporidium parvum
(C.parvum);Bayesian isospora (Isospora belli);Circle sporozoite (Cyclospora cayetanensis);Seemingly
Earthworm ascarid nematode (Ascaris lumbricoides);Ascaris trichiurus (Trichuris trichiura);Ancylostoma duodenal
Nematode (Ancylostoma duodenale) or Necator americanus (Necator americanus);Excrement class round wires bend roundworm
(Strongyloides stercoralis Toxocara), for example, Toxocara canis (T.canis), belascaris cati (T.cati);
Baylisascaris (Baylisascaris), for example, racoon Beyliss ascarid nematode (B.procyonis);Trichinella
(Trichinella), for example, trichina(Trichinella spiralis) (T.spiralis);Dracunculus (Dracunculus), for example, Medina is imperial
Nematode (D.medinensis);Filaria class (genus Filarioidea);Wuchereria bancrofti (Wuchereria
bancrofti);Cloth Lu Geshi filarias (Brugia), for example, Malaysia Bu Lugeshi filarias (B.malayi) or Supreme Being's line Bu Luge
Family name filaria (B.timori);Capstan filaria (Onchocerca volvulus);Loa loa (Loa loa);Heart worm
(Dirofilaria immitis);Schistosoma (genus Schistosoma), for example, Schistosoma japonicum
(S.japonicum), flat blood fluke (S.mansoni), schistosoma mekongensis (S.mekongi), interleaves blood fluke
(S.intercalatum), Schistosoma haematobium (S.haematobium);Lung fluke (Paragonimus), for example, Wei Shi lungs are inhaled
Worm (P.Westermani), Pagumogonimus Skrjabini (P.Skriabini);Clonorchis sinensis (Clonorchis sinensis);Liver slice
Fluke (Fasciola hepatica);Liver fluke species (Opisthorchis sp);Fasciolopsis buski
(Fasciolopsis buski);Fish tapeworm (Diphyllobothrium latum);Tapeworm (Taenia), for example,
Beef tapeworm (T.saginata), taeniasis suis (T.solium);Echinococcus (Echinococcus), for example, particulate spine
Ball tapeworm (E.granulosus), Echinococcus multilocularis (E.multilocularis);Pico+ribonucleic acid+virus
(Picornaviruses), rhinovirus (rhinoviruses) Yi Ke is viral (echoviruses), Coxsackie virus
(coxsackieviruses), influenza virus (influenza virus);Paramyxovirus (paramyxoviruses), example
Such as, 1,2,3 and 4 type;Adenovirus (adenoviruses);Herpesviral (Herpesviruses), for example, HSV-1 and HSV-2;
One herpes zoster virus of varicella (varicella-zoster virus);(people) thermophilic T lymphocyte virus (human T-
Lymphotrophic virus) (I types and II types);Arboviruse (Arboviruses) and arenavirus
(Arenaviruses);Alphaherpesvirinae (Togaviridae), flaviviridae (Flaviviridae), Bunyaviridae
(Bunyaviridae), Reoviridae (Reoviridae);Flavivirus (Flavivirus);Hantavirus
(Hantavirus);Viral encephalitis (Viral encephalitis) (alphavirus (alphaviruses), for example, in committee
Auspicious drawing equine encephalitis (Venezuelan equine encephalitis), eastern equine encephalitis (eastern equine
Encephalitis), western equine encephalitis (western equine encephalitis)));Viral hemorrhagic fever (Viral
Hemorrhagic fevers) (filamentous virus (filoviruses) is [for example, Ebola virus (Ebola), marburg virus
(Marburg)] and arenavirus (arenaviruses) is [for example, Lassa virus (Lassa), machupo virus
(Machupo)]);Smallpox (Smallpox) (smallpox (variola));Retrovirus (retroviruses) is for example, people exempts from
Epidemic disease defective virus 1 and 2;6,11,16,18,31,33 and 35 type of human papilloma virus (human papillomavirus) [HPV].
In various embodiments, probe is that optionally, the polynucleotide sequence is for polynucleotide sequence
Selected from the feature by following group of groups of biology:Pseudomonas aeruginosa (Pseudomonas aeruginosa), proteus mirabilis
(Proteus mirabilis) produces the sour primary formula bacterium of Cray (Klebsiella oxytoca), Klebsiella pneumoniae
(Klebsiella pneumoniae), Escherichia coli (Escherichia coli), Acinetobacter baumannii (Acinetobacter
Baumannii), serratia marcescens (Serratia marcescens), clostridium perfringen (Enterobacter
Aerogenes), enterococcus faecium (Enterococcus faecium), vancomycin resistant enterococci (vancomycin-
Resistant enterococcus (VRE), staphylococcus aureus (Staphylococcus aureus), methicillin-resistant
Staphylococcus aureus (methecillin-resistant Staphylococcus aureus) (MRSA), grass green hammer
Bacterium (Streptococcus viridans), Listeria monocytogenes (Listeria monocytogenes),
Enterococcus species (Enterococcus spp.), streptococcus group B (Streptococcus Group B), streptococcus group C
(Streptococcus Group C), streptococcus group G (Streptococcus Group G), streptococcus group F
(Streptococcus Group F), enterococcus faecalis (Enterococcus faecalis), streptococcus pneumonia
(Streptococcus pneumoniae), staphylococcus epidermis (Staphylococcus epidermidis), vagina adds moral
Receive bacterium (Gardenerella vaginalis), Micrococcus species (Micrococcus sps.), haemophilus influenzae
(Haemophilus influenzae), Diplococcus gonorrhoeae (Neisseria gonorrhoeee), OK a karaoke club catarrhalis
(Moraxella catarrahlis), Salmonella species (Salmonella sps.), Chlamydia (Chlamydia
Trachomatis), peptostreptococcus productus (Peptostreptococcus productus), peptostreptococcus anaerobius
(Peptostreptococcus anaerobius), lactobacillus fermenti (Lactobacillus fermentum), slow true bar
Bacterium (Eubacterium lentum), Candida glabrata (Candida glabrata), Candida albicans (Candida
Albicans), Chiamydia species (Chlamydia spp.), campylobacter species (Camplobacter spp.), salmonella
Species (Salmonella spp.), smallpox (smallpox) variola major (variola major), Yersinia pestis
(Yersina Pestis), herpes simplex virus I (Herpes Simplex Virus I (HSV I)) and herpes simplex virus
II(Herpes Simplex Virus II(HSV II))。
In various embodiments, probe is that optionally, the polynucleotide sequence is B for polynucleotide sequence
The feature of group of streptococcus (Streptococcus).
PCR- i.e. with is carried out on sample PCR may include under thermal cycle conditions heat PCR reagent mixture and in
Polynucleotides sample, the thermal cycle conditions be suitable for from the polynucleotides sample of neutralization generate PCR amplification son;By the more of neutralization
Nucleotide sample or its PCR amplification be that selective at least one probe contacts for polynucleotide sequence;By neutralization
Each of polynucleotides sample and negative control polynucleotides independently connect with PCR reagent mixture under thermal cycle conditions
It touches, the thermal cycle conditions are suitable for independently generating PCR amplification and negative control multinuclear glycosides of the polynucleotides sample of neutralization
PCR amplification of acid;And/or by the polynucleotides sample of neutralization or its PCR amplification and negative control polynucleotides or its PCR
Amplicon be that selective at least one probe contacts for polynucleotide sequence.
In various embodiments, the one or more that the method that PCR is carried out on sample can also include the following steps:
Heat the biological sample in microfluid box;It it is about 20 kPas to 200 kPas or one in the pressure difference compared with environmental pressure
Biological sample in a little embodiments under about 70 kPas to 110 kPas of pressure difference in pressurization microfluid box.
In various embodiments, can also be included the following steps using the method for apparatus described herein one or
It is multiple:Determine the presence of polynucleotide sequence in biological sample, the polynucleotide sequence corresponds to probe, condition be in and
Polynucleotides sample or its PCR amplification in detect probe;Determine pollution as a result, condition is in negative control polynucleotides
Or detect probe in its PCR amplification;And/or in some embodiments, wherein PCR reagent mixture further includes positive right
It is selective plasmid probe according to plasmid and at least part of the plasmid, the method further includes that determination has occurred and that
PCR reactions, condition are to detect plasmid probe.
Fluorescence detecting system including lens and filter is surveyed with multiple parallel dangers of multichannel box
Can be with integration of compact, super-sensitive fluorescence detecting system is for monitoring from the glimmering of biochemical reaction
Light, this is the basis of nucleic acid amplification method such as PCR.
Therefore, the other side of described device includes the system for monitoring the fluorescence from biochemical reaction.Institute
The system of stating can be, for example, a kind of fluorescence detector, there is the detector absorption band in fluorescent dye selectively to emit
The light detection of the light source (such as LED) of light, the lens for focusing light, and emission band selective enumeration method light in fluorescent dye
Device (such as photodiode), wherein the fluorescent dye corresponds to fluorescence polynucleotide probes or its segment.Alternatively, optics
Detector may include the bandpass filtering diode in the absorption band selectively transmitting light of fluorescent dye (fluorescence probe), and
The bandpass filtering photodiode of the emission band selective enumeration method light of fluorescent dye.For example, fluorescence detector can be configured to
There are independent detection a variety of fluorescent dyes of different fluorescence emission spectrums, wherein each fluorescent dye it is more to correspond to a kind of fluorescence
Nucleotide probe or its segment.For example, fluorescence detector can be configured to it is only in multiple and different positions of such as microfluid box
The vertical a variety of fluorescent dyes of detection, wherein each fluorescent dye correspond to a kind of fluorescence polynucleotide probes or its segment.
In some embodiments, it can be detected from a nanoliter rule for the given detector used in apparatus described herein
The fluorescence signal of mould PCR reactions.Advantageously, detector is formed by cheap element, without moving component.Detector is also arranged to
It matches with microfluid box described further herein, and a part for preferably also pressure application system, such as slides
Lid keeps the box in place.Detector also has the potentiality for 2 or 3 color detections, and by software control
System, the software preferably customized are configured to the information that sampling carrys out self-detector.
The embodiment that Figure 57-59 describes super-sensitive fluorescence detecting system comprising light emitting diode (LED), light
Electric diode and filter/lens, for monitoring the one or more fluorescence signals sent out from microfluid box in real time.Figure 57-
Embodiment in 59 has double Color Detecting Systems, has and the matched Software Component Design of single channel microfluid box.
Detector includes two LED (blue and red, respectively) and two photodiodes.Two LED are configured to a branch of focusing
Light be transmitted on the specific region of the box.Two photodiodes are configured to receive the light of the field emission from the box.
One photodiode is configured to the feux rouges of detection transmitting, another photodiode is configured to the blue light of detection transmitting.
The exemplary read head of the displays of Figure 60 and 61 comprising 2 Color Detecting Systems of multiplexing are such as shown in
Multiple examples of detecting system in Figure 57-59 are configured to match with multichannel microfluid box.Figure 60 shows multichannel tune
The view of the outside of read head processed.Figure 61 is to show how multiple detectors configure in exemplary multiplexing read head,
And with the sectional view of electronic circuit board communications.
Component in Figure 60 and 61 is configured to detect the fluorescence from each channel of the channels 12- box, therefore includes 24
Independently controllable detector is arranged as 12 pairs of same detection elements.Then it is capable of double-colored detection pre-determining per a pair of of element
Fluorescence probe group.It should be understood by one skilled in the art that the detector of other numbers pair and apparatus described herein phase
Hold.For example, 4,6,8,10,16,20,24,25,30,32,36,40 and 48 pairs are also compatible, and can be according to this field
The method and standard configuration that those of ordinary skill understands.
Exemplary optical module
In exemplary embodiment, optics chassis/pressure assembly is placed in shell (in certain embodiments by plastics
It is made) in, it can be located to cover multichannel microfluid box.Shell can optionally have a handle, and the handle can be with
It is easily grasped by the user, and is guided for smooth and easy push and pull.Handle is also used as pressure locking
Device.The horizontal position of shell is sensed in standard-sized sheet and complete forward position, and is reported and arrived control software.Shell and optics bottom
Disk pressure assembly is aligned to the heater cartridges component being located in below microfluid box within 0.010 ".Close installation is for suitable
When heater/pod interface connection be important.Service life of the casing assembly by 10,000 cycle does not reduce in performance,
Middle cycle is defined as:In the case where sliding block is in rearward position, and then handle is locked down in by forward slip
On box, handle is unlocked and returns it to initial rearward position.Whole light path parts should be non-reflective (anodization
, dyeing, molding, etc.) and this feature is not lost for 10,000 cycles.Optical unit is not by from apart from instrument
12 " light intensity of the ruler international candles of <=9,000 in the source that the angle being most likely to occur is placed is penetrated with light to be influenced.It is followed 10,000
Not in photo-detector measurement to reduced performance after ring.
When manufacturing detector module, manufacture accommodates the single channel of two LED sources (blue and amber), and respectively holds
Receive other two channel in a photodiode detector (four holes to drill completely).Two pairs of channel (source and detections
Device) from optical axis measurement be in 43 ° of orientations, and with other pairs of channels being orientated at identical 43 ° in line.Optics chassis
The hole of middle brill is contained with the filter and lens for being properly isolated from object, and specification is described further herein.LED is maintained at
Appropriate location is to prevent from moving, because mechanical alignment is important good source lighting.LED is preferably distortion, until
It harmonizes in the reading channel of two " hot spot " and box.The position must be kept until LED is immovable.Optics chassis can use aluminum
At and be black anodizing.The base pressure surface of optics chassis is smoothed to ± 0.001 on all surfaces ".Optics bottom
Disk is center balance, so that the center of optics chassis power is close to kit center.Pressure assembly (bottom of optics chassis)
The uniform pressure of minimum 1psi is provided in whole heater sections of kit.Optical module may be located remotely from what box was removed and placed
It moves in kit region.The appropriate grinding of optics chassis is preferably to prevent glitch to be emitted to optics PCB.
LED light source (amber and blue) is incident on by bandpass filter and condenser lens on microfluid box.These
LED light source has the minimum output of 2800 milli candle lights (blue) and 5600 milli candle lights (green), and centre wavelength is 470 (blue
Color) and 575 (amber) nanometers, half-peak breadth is no more than 75 nanometer.
LED light excites at least one of the single ventricle on box fluorescent molecular (being initially attached to oligonucleotide probe), makes
It fluoresces.The fluorescence usually will effectively be blocked by the quencher molecule of tight spacing.It will be via the DNA cloning of TAQ enzymes
Fluorescence and quenching molecules and oligonucleotide probe separate, and cannot quench.If the target molecule (DNA sequence dna) of probe is present in sample
In room, then DNA cloning can only occur.Fluorescence occurs when a certain wavelength impacts target molecule.The light of transmitting is different from incident light.It is logical
Green independent emission filter is crossed, blue incident light, which is blocked, leaves the detector.By yellow emission filter, green enters
It penetrates light and the detector is left by similarly retardance.Fluorescence is captured and enters in condenser lens via a propagated,
By filter and travel on very sensitive photodiode.The light quantity of detection increases, because DNA cloning amount increases.
Signal will change with the fluorescent dye used, but peak-to-peak ambient noise should be less than 1mV.Can permanently it pacify in fixed position
5 years or 10,000 cycle should be stablized by being attached to the photodetector of optics chassis, and should be for low-down light level
Sensitively, and with the dark value no more than 60mV.In addition, photodetector must be supplied in the market at least 10 years.Lens
It is plano-convex (6mm detectors and the sources 12mm focal length), there is the flat side against testing cassete on two lens.Filter is just
It should keep stable in normal operational humidity and temperature range.
Filter, such as be surface product by Ou meter Ge optics (Omega Optical) (Brattleboro, VT 05301)
Matter is the optical glass base of F/F per Mil-C-48497A.Individual diameter of the filter with 6.0 ± 0.1mm, 6.0 ±
The thickness and AOI of 0.1mm and 1/2 cone AO1 are 0 degree and ± 8 degree respectively.The hole opened is > /=4mm diameters and by side
Edge is processed into blackening, is mounted in the anodized metal ring of black later.FITC exciter filters are by such as Ou meter Ge light
(Omega Optical) (PN 481AF 30-RED-EXC) is learned to provide.They with 466 ± 4nm cutoff frequency and 496 ±
The initial frequency (cut-on frequency) of 4nm.Transmission be > /=65% peak value and block be:From 503 to 580nm, reason
By upper>/=OD8 averagely passes through 651-1000nm from 501-650nm, > /=OD5, and > /=OD4 and UV-439nm, > /=
OD4.FITC transmitter filters are by for example, Ou meter Ge optics (Omega Optical) (PN 534AF40-RED-EM) provides
's.They will be with the initial frequency of the cutoff frequency and 554 ± 4nm of 514 ± 2nm.Transmission is > /=70% peak value, and
Retardance is:Theoretically 400-504nm, > /=OD8, UV-507nm, > /=OD5, and average 593-765nm, > /=OD4.Amber
Amber color exciter filter is provided by such as Ou meter Ge optics (Omega Optical) (PN 582AF25-RED-EXC).
The initial frequency of their cutoff frequencies and 569 ± 5nm with 594 ± 5nm.Transmission is > /=70% peak value, and is blocked
It is:Theoretically from 600 to 700nm, > /=OD8,600-900nm, > /=OD5 and UV-548nm, > /=OD4.It is amber
Transmitter filter is provided by such as Ou meter Ge optics (Omega Optical) (PN 627AF30-RED-EM).They have
There are the cutoff frequency of 642 ± 5nm and the initial frequency of 612 ± 5nm.Transmission is > /=70% peak value, and blocks and be:It is theoretical
On from 550 to 600nm, > /=OD8, UV-605nm, > /=OD5, and average 667-900nm, > /=OD5.Spacer is complete
Should be that inert and temperature is stablized, and should filter be maintained at exact position and adjustment in portion's opereating specification.Make
Epoxy resin should have optics black and opaque material and the not drying solid of viscous residue.In addition,
It should have temperature and Moisture stability, not apply pressure on the element of holding, and should pacify in such a way
Fill PCB, the mode be it be it is fixed and stablize, do not rotate or vertical height change chance.50% illumination is answered
When falling in sample plane, in the region of 0.1 " (2.5mm) wide × 0.3 " (7.5mm) of the axis along sense channel.Control
" height, although ± 0.010 distance controlling core of region that the fluorescence of chip should not change measuring signal/0.001 more than 0.5%
The nominal height of piece.
Exemplary optical sheet is shown in Figure 62, and anti-for detecting and amplifying the successful chemistry on microfluid box
The fluorescence signal answered, and the intensity of LED is controlled to illuminate box sample on up to four channels using pulse width modulation (PWM)
Product, there are two colors to select for each channel tool.In addition, it passes through LVDS (low-voltage differential signal) SPI (continuous perimeter interface)
Receive to instruct and beams back result data.Panel system includes:+ 12V is inputted;It is exported with+3.3V ,+3.6V ,+5V, and -5V,
Configuration is as follows:+ 3.3V outputs contain linear regulator, for driving LVDS interface, should keep +/- 5% accuracy, and supply
Answer the output current of 0.35A;+ 3.6V outputs contain linear regulator, for driving MSP430, should keep +/- 5% accurate
Degree, and supply the output current of 0.35A;+ 5V outputs contain linear regulator, for driving the positive rail for op-amps
(plus rail) should keep +/- 5% accuracy, and supply the output current of 0.35A;- 5V outputs are supplied from+5V to be received
Its power, the negative rail (minus rail) for driving op-amps and photodetector bias, should keep +/- 1% voltage
Accuracy, and supply the output current of 6.25mA+/- 10%.In addition, panel has 80 ohm source resistance, and mainboard is soft
Part can be such that adjuster output opens/closes.
Mainboard interface is using the single channel of LVDS standards to connect between the plates.This is believed on LVDS interface using SPI
Number occur, the LVDS interface is connected to the main SPI port of control processor.Interface also contains the company for being useful for in-system programming
Continuous port.
The exemplary Systems for optical inspection of Figure 62 is made of control processor, LED driver and optical detection system.In example
In act property embodiment, control processor is by double SPI (one is used for ADC interface for mainboard interface and one) and to be used for
The TI MSP430F1611 for extending SRAM compositions of data storage.There is power monitoring, PWM LED controls and SPI to be connected to for it
The function of ADC and mainboard.LED driver contains NPN transistor switch, is connected to the PWM outputs of control processor, Ke Yijie
By 10mA@12V/LED (amounting to 80mA), and it is to be connected to the single logical of respective LED (one, each color) with 2
Road.There are two channel and by photodetector, highly sensitive photodiode detector, high-gain current arrives optical detection system tool
Electric pressure converter, unity-gain voltage convert amplifier and ADC compositions.In addition, it contains 16 channel ∑s-triangle (merely with preceding
8 channels), it is connected to the second SPI port of control processor.It should be understood by one skilled in the art that other
Element selects and combination can generate the function detecting system consistent with description herein together.
The other advantage and feature of technology herein
Using disposable process chamber, the process chamber has face coat and material character to allow small size, and
The release of open pipes heating, so that the sample concentration in possible minimum volume maximizes.
Multiple samples are allowed to be independently heated but using single moveable magnet platform separated integrated magnetic thermal point
From device.
Reader/disk design allows to be easily placed microfluid box and uses automation distributor a position
The samples of multiple liquid pipette;Relative displacement applies to another position and pressure, for subsequent fast speed heat incubation step
And optical detection.The bottom surface of box is matched with heating surface.Moreover, mobile box and heater generally compare moving detector into out position
More easily.
Moveable read head is designed for the fluoroscopic examination from the channels microfluid PCR.
The aspect of fixator such as combines disposable item comprising seals freeze-dried reagent and close to sealing
The presence of liquid is generally difficult to realize.The laminated material disposed herein makes storage become easier to.
The fixator allows the snap-on of multiple ASR pipes and relevant fluid dispensation method, make across sample pollution most
Smallization, but allow to carry out multiple PCR preparations from single clinical sample.
Software features allow user as rapidly as possible from all 24 samples obtain as a result, or as rapidly as possible from
Preceding 12 samples and then result is obtained from next 12 samples.
It is described herein preparation and diagnostic instrments can make different sample types (such as blood, urine, swab, etc.) simultaneously
It is all handled, even if may each need different temperature, time or chemical reagent.This is by using individualized but phase
The fixator of appearance and what part was realized.
Microfluid box be automatically transported to via box automatic loader the time that user is saved in PCR readers and
Lead to the raising of overall operating efficiency.
Foil is pierced through on liquid line and draws the reliable fashion of liquid.
Moveable read head has the pump moved with it, sensor (pipette detects, power sensing), sample
Diagnostic test device etc., therefore the number for crossing over the control line of instrument movement during use is made to minimize.
Use motor-driven aligning strip, the adjustment accurately and quickly of pipette tip and box ingate.
Embodiment
Embodiment 1:Reagent fixator
The exemplary reagent fixator consistent with being described herein has following size and performance:
● 180mm long × 22mm wide × 100mm high;
● it is made up of polypropylene.
● the 1.7ml of the low adhesion of a snap on system is managed, and is worked as processing tube.
● 3 built-in pipes, the storage as reagent works, as follows:
01 pipes for containing 200-1000 μ l washing buffers (0.1mM Tris, pH8).
The pipe of 01 release solutions (40mM NaOH) containing 200-1000 μ l.
The pipe of the 01 neutralization solution (330mM, pH8.0) containing 200-1000 μ l.
● the pipe built in one works as waste chamber (by holding~4ml waste liquids).
● receive 3 storages of solid reagent container.By the PCR pipe of snap on system 0.3ml or 0.65ml, (it is general independent
Stored in reagent fixator) it is placed in each of these positions, and contain respectively:
Zero freeze-drying sample preparation reagents (dissolving enzymatic mixture and magnetic compatibility pearl).
The PCR of 0 first freeze-drying controls mixture, probe and the primer for the detection of the first target analyte.
0 second freeze-drying PCR control mixture, probe and for the second target analyte detection primer (only in the feelings of selection
It is provided under condition, such as surveys Chlamydia and gonorrhoea from urine examination).
● 4 pipette tips positioned in 4 corresponding jacks.
● pipette tip set:Pipette tip has set/drip disk later from using to help to collect below
Any drop of pipette tip, and also prevent undesirable instrumental pollution.
● handle and snap lock allow item to be readily inserted into, and removing and reliable location are in the bracket.
● one or more label:Upwardly facing positioning to promote to be easy by eye and/or such as bar code reader reading,
It is marked with the one or more of the information of the machine readable analysis for being related to being carried out containing the mankind's.
It should be appreciated that these sizes are exemplary.However, being particularly desirable that ensures, fixator is no more than this
A little sizes so that the holder and device that accommodate one or more reagent fixators will not inconveniently become larger, and can be suitble to
Ground positions in the lab, for example, on bench-top.
Embodiment 2:Disposable reagent fixator manufacture
It can design and be machined simple fixing device can operate and handle multiple.There are five steps, can
To carry out the step to produce the element.Disposable reagent fixator will be placed in fixing device and using artificial
/ electricity multiple liquid relief it is hydraulically full.And then after whole liquid being assigned to the item, exemplary heat sealing equipment is used
Foil is heat sealed to plastics and modifies the foil as needed by (Hix FH-3000-D tack press).It is heated seal by liquid
After onboard, whole beads in pipe can move quickly into item, and pipette tip can be inserted in the corresponding of them
In jack, and it can be marked with fixed bar code.Dry packing can be placed into the blowing for being designed to accommodate 12 fixators
Or in the holder of thermoforming.12 disposable items will be loaded onto in holder and then be sealed with a foil.Hermetic bag will be put
It sets in carton and marks for transporting.
Embodiment 3:The foil of Reagent Tube containing buffer solution seals
Pipe containing buffer solution must be sealed with high-moisture vapor barrier material to keep the liquid over a long time.One
The fixator of secondary property can need the storage life with 1-2, and thus, they should not lose in the period is more than
The liquid volume of the 10-15% with the liquid of volume needed for holding, and keeps the dense of different kinds of molecules present in solution
Degree.Moreover, the material and sealing laminated material that use for the structure of the pipe should not be reacted with liquid buffer.It is special
Plastic laminating material moisture barrier can be provided, but they may must be very thick (being more than 300 μ m-thicks), make puncture
Power shockingly rises or special expensive polymer (such as Aclar).Aluminium foil, even if hundreds of angstroms of thin foil provides effectively
Moisture barrier, but exposed aluminium is reacted with some liquid buffers, such as sodium hydroxide, or even has non-reaction polymer
The aluminium foil of spray-painting may not be able to be subjected to corrosive vapor for a long time.They can pass through minimum pin hole present in coating
It reacts and can cannot function as shielding over time.
For these reasons, the aluminium foil with laminate structures has been identified as suitable shielding, exemplary
Property description is as follows:
1. sealing
It is heat sealed to combination polypropylene strips (seal temperature~170-180 DEG C)
The foil is wrinkle resistant after sealing, rupture and crackle.
2. moisture vapor transmission rate (MVTR)
1 year period of environment temperature and pressure reservoir be less than 10% liquid loss (20 from 200 microlitres of volumes is micro-
It rises).(effective area~63mm of transmission2);About MVTR~0.8cc/m2/ day
3. chemistry
The ability that do not reacted with 40mM sodium hydroxides (pH < 12.6):Foil should have closer to sealing fluid at least
15 microns of thick plastic laminating materials.
The ability that do not reacted with other buffer solutions containing mild detergent
4. piercing through
The ability pierced through using the effective power for being less than 3 pounds of p1000 liquid reliefs
Before puncture, the film of a diameter of 8mm fully supported will not extend beyond 5mm in that orthogonal direction.
After puncture, foil should not seal the pipette tip of pipette circumference.
5. other feature
It is pin-free
There is no bubble in more laminate structures.
Embodiment 4:It pierces through plasticising laminated material and withdraws the mechanism of liquid buffer
The aluminium laminated material containing plastic foil described elsewhere herein is sufficiently used for not with corrosive reagents such as
Buffer solution reaction containing NaOH, and with advantageous puncture property and it is used as moisture barrier.However, during puncture, it
Show some other difficulties.Aluminium foil tends to be broken into the irregular polygon pattern more than liquid relief pipe diameter, however plastics
Film tends to be enclosed in around pipette tip, has minimum clearance between pipette and plastic foil.Bore dia in plastic foil
Similar to the maximum gauge for the pipette for having already passed through laminated material.This packaging of pipette causes distribution and pipetting
Difficulty, unless there are discharge orifice, allowable pressure balances other than the pipe between the pipe inner air.
Successful fluid liquid relief strategy is as follows:
1. being penetrated through laminate structures and making pipette close to the bottom of Reagent Tube, to be produced in laminated material
Raw hole is almost big as the maximum gauge of pipette (for example, being~6mm for p1000 pipettes)
2. pipette is withdrawn short distance upwards, so that small ring row discharge hole stays between pipette and laminated material.
The maximum outside diameter of minimum outer diameter and 6mm of the p1000 pipettes with 1mm, and the conical section of pipette is about 28mm long.One
Hundred microns of discharge orifice thickness is enough to generate reliable discharge orifice.This, which corresponds to, is inserted into the pipettes of 5.8mm diameters, it week
Enclose the ring for leaving 0.1mm.
3. withdrawing fluid from the pipe.It should be noted that for sample preparation procedure, the pipe is designed to keep comparing from it
More fluid necessary to withdrawing.
Embodiment 5:Foil pierces through and the dissolving of freeze-dried reagent:
The container of freeze-dried reagent about fixator described herein offer is usually by non-plasticizing aluminium foil (that is, not being
Laminated material for sealed reagent pipe) sealing.Even if pipette is moved to the bottom of the tube, aluminium foil is when piercing through pipette
Also it is broken into irregular polygon pattern and leaves air discharge ports.In order to save reagent, it is desirable to solubilising reagent
And the amount extracted out from pipe is made to maximize.In order to realize this, by star burr (star-shaped) pattern be placed on container bottom with
The flowing velocity between the liquid volume of withdrawal and burr is set to maximize.
Dissolving and withdraw fluid exemplary steps are as follows:
1. piercing through pipette and distributing fluid far from freeze-dried material.If pipette arrived freeze-dried material it is horizontal in the following,
It will enter pipette and can cause the obstruction for coming from the liquid flow of pipette.
2. freeze-dried material is made to dissolve the several seconds.
3. movement pipette contacts downwards the burr bottom of the pipe
4. executing the absorption of enough numbers and the operation (4-10) that spues being the reagent to be thoroughly mixed with liquid buffer.
5. withdrawing whole reagents and mobile pipette being it to be assigned in next processing tube.
Embodiment 6:The material and surface nature of lysis pipe
Material, surface nature, surface finish have profound influence for the measurement sensitivity of progress.In clinical application,
It needs to detect with being determined in the background of billions of other molecules as low as the DNA/RNA (~1ml volumes) of 50 copies/sample,
Some strong inhibitions PCR in other molecules.In order to realize these high level of sensitivity, it is necessary to selection reaction pipe surface
And the material on the surface is with the minimal adhesion with polynucleotides.Injection molding tooling is being generated to generate these plastic tubes
Period, the intrinsic surface generated by mechanical processing can have big surface area, this is because cut mark arrives greatly some tens of pm
Peak and valley.These surfaces must be polished to SPI A1/A2 finish (minute surface finishing) to remove microcosmic surface imperfection.
Moreover, the presence of these microcosmic paddy will retain magnetic beads (0.5-2 μ) in the position being not intended to and generate irregular property
Energy.In addition to actual surface roughness, surface hydrophobic/existing surface molecular can cause polynucleotides to be sticked to be not intended to
Position and the sensitivity for reducing overall test.In addition to basic material use, such as homogeneity polypropylene and other polymer, at this
The certain material used during a little pipe die modelings, any additive that such as parting compounds or help manufacture can be for reaction
Executing has profound influence.
Embodiment 7:Liquid distributor
About Figure 18,19A-C and 63, exemplary liquid distributor is connected to rack, and receive via cable 1702
Instruction.Bar code scanner 1701 is mounted on a face of liquid distributor.Rack is mounted in horizontal rail 1700 to carry
For the movement on the directions x-.The track of orthogonal configuration is not shown that provide the movement on the directions y-.Liquid distributor includes
The power pump 1800 of computer control is connected to the fluid distrbution manifold with correlation computer control valve adjusting 1801
1802, and pipette that 4- with independent spring head 1803 is upward.Fluid distrbution manifold has nine Lee Co. solenoids
Valve 1801, the air stream that control passes through pipette tip:Two valves of each pipette, and it is discharged other the one of the pump
A valve.Bar code reader 1701 can definitely detection sample cell, reagent is disposable and the box of microfluid.It will scanning
Device is installed to z-axis so as to position it to read sample cell, item and box bar code.
Embodiment 8:Integrated heater/separator
In Figure 64, it is shown that exemplary integrated magnetic separator and heater assembly.By magnetic separator 1400 and add
12 heat blocks including being arranged parallel to each other are made in hot device assembly 1401.Each heat block 1403 is made of aluminum, and has
L- shapes construct, and have the u-shaped entrance for receiving process chamber 1402.By each heat block 1403 metal strip 1408 and spiral shell
Nail 1407 is fixed and is connected.Magnet 1404 is rectangle neodymium block (or other permanent rare earth materials, K&J Magnetics, field of force magnetic
Body (Forcefield Magnetics)), configuration is behind each heat block 1403 and installs on a support element.Gear
1406 convey rotational energy so that motorized shaft 1405 improves relative to each heat block and reduces magnet from motor (not shown)
1404.Motor is computer control, with the speed moving magnet of 1-20mm/s.Described device further includes printed circuit board
(PCB) 1409, it is configured to make heater assembly that heat is apply independently to each process chamber 1402 when receiving instruction appropriate.
In exemplary embodiment, described device also includes the temperature sensor and power resistor being connect with each heater block.
Embodiment 9:Exemplary software
May include two extensive part-user interfaces and device with the exemplary software that device herein uses
Firmware.User interface software can in order to the aspect that interacts with user such as-input patient/sample message, monitoring surveys
Examination process, fault alarm, printing test by result as a result, upload to database and update software.Device firmware can be practical
Run the low-level software of the test.Firmware can have can be with the general part of independent test and for ongoing survey
Examination is the part of specificity.Test specificity portion (" regulation ") can specify that microfluid operation and their instruction to realize
The test.
Figure 65 A and 65B show the screen interception from programming interface and the monitoring of real-time heat sensor and fluorescence detector.This
A real-time clock performance monitoring is for test purposes;User is not visible in ultimately constructed.
User interface:
Medical grade LCD and touch panel unit may be used as user interface, and readily behaviour is provided via the user interface of diagram
Make and small fault look-up command.LCD and touch screen are it has been specified that ensure the compatibility of all surfaces and usual detergent.With
The integrated bar code scanner of analyzer can be configured to bar code (regulation box type, lot number, the term of validity that scanning is detached from box
Limit), and if can get, the patient from one or more sample cells and user ID.
Embodiment 10:Exemplary preparation facilities
The product be 24 clinical samples can be automatically processed within about half an hour with produce purification nucleic acid (DNA or
RNA instrument (Figure 66)).The nucleic acid of purification can be handled in individual amplification-detection machine to detect certain target nucleic acids
In the presence of.Sample handled in combining disposable item, by sample preparation principles of chemistry preloaded, and will finally be purified
Nucleic acid is assigned in PCR pipe.Fluid operation is started by the head of pipette moved with xyz racks.(Figure 67)
The system has following sub-systems:
Two sample treatment holders of ■, each holder handle up to 12 clinical samples in combining disposable item
■ magnetic separators-and-pipe heater component (24 heating stations)
Tetra- probe liquid dispensing heads of ■
■ moves the 3- axis platform framves of head of pipette
The Peltier cooling pcr- pipes that ■ receives the DNA/RNA of purification keep station
■ controls electronic device
■ bar code readers
Operation:User will obtain the Work List of each sample, they whether want to extract the DNA of each clinical sample or
RNA.Each sample type (DNA or RNA) is placed on the bracket and be used for sample cell, and user is primary by composite reagent
Property article (DNA or RNA processing) slides into the respective channel of holder.Combining disposable (fixator) will have in advance
It is packaged in whole samples reagent preparation therein, processing tube and disposable pipette.Once all disposable article dresses
It is downloaded in holder, then the holder is placed on its position on instrument.Open pcr pipes are placed on Peltier cooling tube
In fixator, the nucleic acid finally purified there will be assigned.Then, user closes the door of instrument, then uses GUI (figures
Show user interface) start sample treatment.
Then the function of instrument testing whole subsystem reads the bar code of sample cell and composite reagent disposable.
It is measured with any mismatch for the Work List being pre-stored in, and failure is marked, if necessary.Then pass through instrument a series of
Liquid handling, heating, Magnetic Isolation is to complete the sample preparation steps of each clinical sample and be output to the nucleic acid of purification
In PCR pipe.The basic step that each sample treatment includes is sample lysis, nucleic acid is collected into magnetic affine pearl, washing
Magnetic beads discharge nucleic acid to remove impurity, from magnetic beads, neutralize discharged DNA and are assigned in final PCR pipe.These pipes
4 DEG C are maintained at until handling whole samples, and user takes downstream processes of the pipe for nucleic acid away.
Embodiment 11:Exemplary diagnostic device
The device combined with related consumptive material automatically carries out all aspects, including sample preparation of nucleic acid test, expands, and
Detection is up to 48 sample/hours, and preceding 24 results can obtain in less than 1 hour.The system is easy to use.Operator will
The part of Patient Sample A is simply distributed in the dedicated pipe containing pre-packaged buffer solution.Dedicated pipe is put into sample branch by operator
In position on frame.Then operator loads disposable plastics reagent strip for the appropriate test in holder.In described device
The middle unique other consumptive materials used are the microfluid PCR boxes for being expanded and being detected;Each box is able to carry out up to
12 PCR test, and can once box-packed be downloaded to two in analyzer.If described device needs new PCR boxes, described
Analyzer will be prompted to operator and load the box.Then, analyzer will be prompted to operator and close lid to start test.All consumptions
Material and sample cell are composed of bar code for specific sample identification.
Prepared by sample lysis and DNA, would require about half an hour for the complete operation of 24 samples, be by analyzer
Automation and liquid operating element use to be located at and combine regulation in disposable plastic strip and reagent carries out automatically.So
Described device automatically mixes sample and PCR reagent afterwards, and injects the mixture into box, and it is automatic will to be integrated PCR machines
Processing.Quickly PCR and detection need to be less than 20 minutes in real time.As a result, it will automatically be obtained when completing PCR, it is shown in
On instrument touch screen, hospital information system is printed or is transmitted to, such as specified by user (or supervisor of user).
Each instrument can be up to 24 samples with single treatment, amount to the logical of 48 samples per hour after the first operation
Amount.Analyzer is slightly less than 1m wide, and is easily mounted on standard laboratory platform.Can use included bar code stick and
Touch screen manages all operationss of the equipment.Analyzer can with laboratory information system, hospital network, PCs, printer or
Keyboard is engaged by four USB interfaces and ethernet port.
Described device has following features.
Sensitivity:Described device limits the detection of DNA or RNA with~50 copies.(and can have as low as 25-
The detection limit of the DNA/RNA of 30 copies).
The cost of each test:Due to HandyLab reagents, the miniaturization of box and other consumptive materials, simplified attribute, often
The Item Cost of one test will be relatively low and very competitive.
Automation:It is contrasted with the NAT systems of electric current " automation ", all needs a degree of quite extensive skill
The interaction of art expert and system, by using integrated test and sample extraction, preparation, amplification and the complete set of detection
At device herein will provide higher levels of automation, and correspondingly reduce technical specialist's time and required technology
Level, therefore advantageously influence total labour cost.
Throughput:Throughput is defined as how much system can be tested in the time of specified rate.On an average, the dress
45 tests will be run per hour by setting.
Obtain the time of the first result:Under hospital environment, the time for obtaining the first result is especially important consideration.Institute
First 24 will be generated as a result, and generating other 24 results per half an hour thereafter in less than one hour by stating device.
Random access and STAT:Random access is to run multiple tests together in single operation and be placed on sample
The ability of unallocated position on analyzer.Equally, with chemistry and immunoassay system, it is desirable to can be transported at one
Row increases test after having been started up.This is frequently referred to as " true random access ", because being provided about can be with for user
Any test is run, complete flexibility in operation when can be added in the where of analyzer and new sample.STAT is
The sample of fast results as far as possible is needed, therefore priority is given in test instructs on analyzer.Now, substantially all
Chemistry and immunoassay analyzer are true random access and provide STAT performances.However, for NAT, considerably less is
System provides any random access or STAT performances.Instrument herein will provide random access and STAT performances.
Menu:The number and type that can be used for the test of analyzer are very important factor in selection system aspects.This
Device in text configures popup menu strategy, is related to the mixture of large volume, " standard " combined with new high value test
Nucleic acid is tested.
Described device can be such that 24 clinical samples automatically handle with purifying nucleic acid, and the DNA/RNA of purification and PCR is tried
Agent mixes and executes real-time PCR in microfluid box to provide result in one hour for sample.Exemplary device has
There are two PCR readers, can each run 12 channel microfluid boxes, use the optics with special dichroic optica detecting system
System.Figure 68, Figure 69.
Described device has following sub-systems:
● two sample treatment holders, each holder handle up to 12 clinical samples in combining disposable item
● magnetic separator-and-pipe heater component (24 heating stations)
● four probe liquid dispensing heads
● the 3- axis platform framves of mobile head of pipette
● two PCR amplification-measuring stations can each run the special 2- of the channels 12- microfluid box and each channels PCR
Color optics detecting system.
● control electronic device
● bar code reader
The photo of external (face-up) and inside is respectively in Figure 70,71.
Operation:User will obtain the Work List of each sample, and whether they will detect certain about each clinical sample
A little target analytes (such as GBS, Chlamydia, gonorrhoea (gonnorrhoea), HSV).Sample cell is placed on holder, and right
In each sample, user slides into the disposable object of composite reagent (analyte specificity) in the respective channel of holder.Group
It closes disposable and will have and has been prepackaged in whole samples reagent preparation therein, PCR reagent, processing tube and disposable
Pipette.Once whole disposables are loaded into holder, then the holder is placed in its position on instrument.
Then, two channels 12- microfluid PCR boxes are placed in two disks of PCR readers by user.Then, user closes
Then the door of instrument uses GUI (graphical user interface) to start sample treatment.
Then the function of the instrument testing whole subsystem reads the bar code of sample cell, the disposable object of composite reagent
Product and microfluid box.It is determined with any mismatch for the Work List being pre-stored in, and marks failure, if necessary.
Then, the instrument undergoes a series of liquid handlings, heating, and Magnetic Isolation is walked with the sample preparation for completing each clinical sample
Suddenly, the nucleic acid of purification is mixed with PCR reagent and final mixture is assigned in the channel of microfluid box.Will be microcosmic
After fluid box is loaded with final PCR mixtures, box disk is mobile and arranges the box in reader, and Systems for optical inspection will
The box is squeezed against microfluid PCR heater surfaces.Valve on chip is started to close reaction mixture, is then opened
Beginning thermal cycle is to cause PCR reactions.In each PCR cycle (reaching 45 cycles), the fluorescence from each channels PCR is by light
Learn what detecting system (the 2- colors/channels PCR) detected, and final result is measured based on threshold cycle (Ct).
The sample preparation steps of 24 samples are carried out in about 40 minutes and PCR reaction in about 20 minutes into
Row.
Sample reader:
When together with HandyLab microfluids (test) box in use, reader be executing up to 12 by PCR method (in real time
PCR) the functional test of suitably prepd Patient Sample A.Each equipment will use two reader components for amounting to up to 20
Four tests.(Figure 72 A and 72B) interacts the operational design of reader for minimum user, it is only necessary to load and unload
Carry testing cassete.During " loading disposable " sequence, reader will provide the disk of motor drive, disposable for installing
Box.The small knob being slidably disposed in disk front, the guard cover that spring loads will increase, and testing cassete is allowed correctly to be set with
It is in place.Then reducing covering, oneself is locked in disk frame until knob, during sample loading sequence described in fixation
It box and prevents from moving.
Once via the sample prepared by being distributed in testing cassete is pipetted into, the disk will retract into reader, will
Testing cassete is accurately located under the chassis of optical module.Then, optical module will pass through the stepping motor of lock-bit screw drive
It is reduced until being contacted with testing cassete.At this point, testing cassete is located in the target position on heater assembly or more 1/
8″.When moving downward lasting, testing cassete in the disk and its fixator compress on disk frame bounces that (these are subsequent
What is used is located at so that the box is returned to its normal position and can be removed during disk operates on heater assembly
Packaging conductive wire connects).Once being contacted with heater assembly, then the movement of testing cassete and optical module is realized, and enclosing
The minimum value of 2psi is obtained on 2/3rds of the channels PCR and the box region of their regulating gate.At this point, using
Heater assembly carries out the test of box, is measured with airborne Optical devices, and controls many via software and electronic device, with
It is carried out with the same way being currently running on similar HandyLab instruments.
Once function test is completed, main motor increases optical module, is released stress on testing cassete to return to
Its normal position.When control, the disk is supplied to consumption by the disk motor operated in a manner of holder-and-pinion gear
Person, for box removing and abandon.When disk is located in extended position, it be suspended in the support member on device chassis it
On.The component prevents the box from being slided by fixator in disk during loading and sample ought be pipetted into disposable box
When be used as support.It also provides in the support member, is risen during removing and the promptly auxiliary lever of disposable box.
Whole elements that the disk and support member and box rise auxiliary can be moved by consumer, not have to tool, for easily
It cleans and installs again.
Microfluid PCR heater members:
Microfluid PCR heater members include the chip glass of the micro-heater and sensor with lithographic definition, with
Heat is accurately provided for starting valve and executing required thermal cycle to execute real-time PCR reactions.Wafer surface, which has, to be used for
The heating region of the special independent control in the channels every PCR in the microfluid box.For the box of 12- upward (12-up), deposit
In 12 PCR sector domains, and for the upward boxes of 24-, there are 24 PCR heating regions.It will be independent using gold or aluminum conductor connection
Heater and sensor be electrically connected to printed circuit board.The sealant of acclimation to heat provides physical protection for conducting wire connection.Although
The present apparatus manufactures on chip glass, but heater can be produced on to glass and carry silicon wafer and other polymeric base layers
On.Each base can provide the heat and the relevant specific advantages of mechanical performance with it.It, can be in addition to using photolithography method
Using the electronic component that can be purchased off the shelf such as source resistance, Peltier, transistor assembles this heating base, by each element
Upper heating surface keeps in the same plane, to heat and providing microfluid box.The temperature school of each temperature sensor
Quasi- value can be stored in the EEPROM being co-located in heater PC plate or other storing apparatus.
The channels 12- box:
This 12 channel box is identical Basic Design, describes the US provisional patent proposed on November 14th, 2006
In application serial 60/859,284, there is following modification:PCR volumes are increased into 4.5 μ l from 2 μ l, lead to input volume from 4 μ l
Increase to 6 μ l.Ingate is moved several millimeters to allow the 2mm in the box to harmonize the sky of protrusion far from box protrusion
Between.Similar adjustment protrusion further includes in the other edge of box.(Figure 76)
Shell:
The design of crust of the device must satisfy following requirements:Consumer safety attributes during operation;Power is provided and is led to
Believe the channel of interface;Air is provided to enter, leave and filter;There is provided the one-handed performance that is used to open for the installation of material and
It removes;In conjunction with salable aesthetics.
It is cooling:
The cooling of device will combine shell and overall system design to ensure all components for needing air in flow path
Within or receive turn to air.
Current concept is to be used for air intake, to be located on the bottom of inferoanterior panel.Then air will pass through can
Clean filter enters described device later.Sheet metal element will make air guided to disposable holder and main power source
The two.Then, air will be directed through card mount, surround reader, and will be exited through and provided in cover top portion
Slot.
Base plate
XYZ grades and frame are installed to base plate in one way, wherein in the grade, it will between box and disposable
Do not misplace.Shell is installed to base plate.The final design of shell determines the bolt hole pattern for installation.Bottom plate is installed to
Base plate with insulator.All other plates are installed to bottom plate.Disposable is rack-mount, and the holder can be with
It is moved to base plate from the bracket of installation.Reader bracket bolt is fixed to base plate.The final design of reader bracket determines
Bolt hole pattern.Power supply is installed to base plate.Base plate is extended on width and length under whole instruments.
Embodiment 12:Exemplary high efficiency diagnostic device
More height multiplexing embodiment can also be such that 24 clinical samples are processed automatically with purifying nucleic acid, will carry
Pure DNA/RNA is mixed with PCR reagent and is executed real-time PCR in microfluid box.The product is read with single PCR
Device has scanning read head, can be read from the channels every PCR and be up to 4 different colors.Box has 24 channels PCR, can
So that single whole 24 clinical samples of box operation.In addition, the product has the automatic loader of box, wherein the instrument will come from
The PCR readers of box packaging are loaded into instrument automatically, and used box is discarded into waste material disk.Figure is shown in figure
In 73 and 74.
Described device has following sub-systems:
Two sample treatment holders of ■, each holder handle up to 12 clinical samples in combining disposable item
■ magnetic separators-and-pipe heater component (24 heating stations)
Tetra- probe liquid dispensing heads of ■
■ moves the 3- axis platform framves of head of pipette
Single PCR amplification-the measuring stations of ■ can run the channels 24- microfluid box and scanner equipment and be come with detecting
Up to 4 kinds of colors from each channels PCR.
■ is by the box-packed automatic loader equipment being downloaded in PCR detection devices of the channels the 24- microfluid from case.
■ controls electronic device
■ bar code readers
Operation:User will obtain the Work List of each sample, and whether they will detect certain about each clinical sample
A little target analytes (such as GBS, Chlamydia, gonorrhoea, HSV).Sample cell is placed on holder, and for each sample, is made
User slides into composite reagent disposable (analyte specificity) in the respective channel of holder.Combine disposable
To have and be prepackaged in whole samples reagent preparation therein, PCR reagent, processing tube and disposable pipette.One
Denier whole disposable is loaded into holder, then the holder is placed in its position on instrument.Then, user
The door of instrument is closed, then GUI (graphical user interface) is used to start sample treatment.
The function of instrument testing whole subsystem, and it is logical then to read sample cell, composite reagent disposable and 24-
The existing bar code of road microfluid box.It is measured with any mismatch for the Work List being pre-stored in, and failure is marked, such as
Fruit is if necessary.Then, the instrument undergoes a series of liquid handlings, and heating, Magnetic Isolation is to complete each clinical sample
The nucleic acid of purification is mixed with PCR reagent and final mixture is assigned to the channels 24- microfluid box by sample preparation steps
Channel in.After loading microfluid box with final PCR mixtures, by automatic maneuver of the box in PCR readers
Propeller is mobile and arranges.Then Systems for optical inspection squeezes the box against microfluid PCR heater surfaces.By core
The valve of on piece starts to close reaction mixture, then starts thermal cycle to cause PCR reactions.(reach in each PCR cycle
45 cycles), the fluorescence from each channels PCR is detected by Systems for optical inspection (the 2- colors/channels PCR), and most
Eventually the result is that based on threshold cycle (Ct) measurement.Then used box is released automatically and arrives waste material box container.
Microfluid box is stored in box packaging (maximum 24 boxes), and once whole boxes from packaging are used up,
Then the instrument warning user replaces box and packs and empty waste material box container.
The channels 24- box
The channels 24- box has the channels 12PCR of two rows.Multiple views are shown in Figure 75-77.The box has 3 layers,
Laminated material, base, and label.The label is shown in two pieces.Each channel has liquid inlet port, and primary
Property pipette engagement;4 microlitres of PCR reative cells (1.5mm wide, 300 microns of depths and about 10mm long) in PCR reactors and go out
Two micro-valve doors on the either side of mouth floss hole.Micro-valve door usually opens and closes the channel on startup.More than 6 μ l
In the case that fluid is assigned in the box, outlet opening can make additional liquid (~1 μ l) include in the fluid passage.
Circular cone is made in the ingate of the box in shape, and has the diameter of 3-6mm at top, to ensure pipette
It can easily be dropped in conical bore by fluid-dispensing head.Once pipette drops within circular cone, cone shape guiding moves
Liquid pipe and mechanical seal are to provide fault-free distribution or withdraw in fluid to the box.Kong Yue great, its better and pipette pair
Standard, however, the present inventor needs to make pitch-row and shifting between the maximization of the ingress port number within box width and retaining hole
Distance between liquid pipe is compatible.In this special design, the distance between pipette is the loading hole in 18mm and the box
The distance between be 8mm.Therefore, it during a batch operation, is pipetted into channel 1,4,7,11;Followed by channel 2,5,
8 and 12, etc..
The height that the height of conical bore is kept below to protrusion in the box, to ensure that it is prominent that the box can be stacked on
Go out on part.Protrusion in two long sides of the box can stack the box, have minimum between two stack of cassettes
Surface contacts, and also helps from box packaging to lead out into the box in reader (refering to Figure 28-33).
The automatic loader of box
The automatic loader of box is made of the position of the packaging for correctly locking 24 microfluid boxes, pre- to be stacked on bullet
(for example, Figure 33) in the box that spring loads.The case has structural detail on side, to positioning and can lock the packing list
In automatic loader (Figure 33).In order to load new case, sliding members is moved to the left side of automatic loader by user, will
The case is placed and promotes in slot and discharge slide lock so that the case to be maintained to its correct position.When the case needs
When to be replaced, the spring supports for being loaded in bottom portion push up the case.Spiral bullet in the box package base is provided
Spring is promoted against the box, and can continuously promote the box with 4 to 20 pounds of power.
The existence or non-existence of box is by reading the barcode detection at the top of the box, if present.
In order to start PCR operations, PCR reaction mixtures are assigned in automatic loader required in the box of top by head of pipette
In the channel of number (for example, Figure 28).Top box from automatic loader case is advanced in two tracks by propeller, described
Box is directed in PCR readers by track.Then calibrating position box being advanced under reader uses stepping motor by light
Department of the Chinese Academy of Sciences's part moves down, and the box is promoted against micro-heater surface.The bottom of optical component (orifice plate) has on side
There is protrusion, so that the box is precisely aligned against the hole.Stepping motor shifts the box onto pre-calibration position (for example, figure
30), the minimal-contact pressure of 1psi is provided in the heating surface of microfluid box.
After PCR reactions are completed, stepping motor moves up 5-10mm far from the box, releases contact and makes
Box moves in its guide rail.Propeller is activated, and it releases the box to box waste material container (for example, Figure 32).At this
After a step, propeller moves back to its original position.In its period that moves backward, propeller can rise in box packaging
On at the top of box, because it has degree of angular freedom (referring to figure).Torsionspring ensures that propeller returns to horizontal position so that it is right
Next box in sequence to promote.Propeller is mechanically connected to Timing Belt.It can be by making gear motor deflecting
The mobile Timing Belt in either direction.Propeller is installed to sliding block arrangement, is only moved on an axis to limit it
(see for example, Figure 31).
Box propulsive mechanism can also be made and the box from automatic loader case is not only advanced to test position, Er Qieyong
In it is moved back to automatic " loaded " position.This can be such that not used channel in microfluid box is transported for next PCR
In row.
Once the automatic carrying case of box is also designed so as to, using whole boxes, can easily to recycle the case
Or new box is added to it.This reduces the cost for consumer and manufacturer.
Reader
Reader is made of optical detection apparatus, can be squeezed against the channels 24- microfluid box, so as to logical with PCR
Road optically interface, and opposite microfluid heater base extrusion box (Figure 78).The bottom of optical component has 24 holes
(12 holes of two rows), are similar in the size closest to the PCR reactors of the box.Orifice plate is by low Poison material
It is made, the black aluminium of such as anodization, and during operation, so that total background fluorescence is minimized, while making to be only from PCR reactors
Phosphor collection maximize (Figure 79 A and 79B).Orifice plate bottom tool helps two that are properly aligned with box there are two oblique edge
Edge, so as to the hole with PCR reactors to straight.(Figure 80,81)
Optical detection apparatus (amounting to 8 detection devices) is assembled and is installed on the sliding rail inside optical box, with
Can on the hole scanning optical apparatus (Figure 82).The light of a certain wavelength can be excited and focus on PCR by each equipment
On reactor, and will be in the transmitting phosphor collection to photodetector of specific wavelength.By using 4 kinds on the channel of 4, top
Different colours, and 4 kinds of colors are repeated in foot passage, whole scanners can scan up to 4 from the channels every PCR
Kind color.
Optical component can be machined and be anodised from aluminium or be injection moulded using low Poison black plastic
(Figure 83).Injection moulding can significantly decrease unit cost and also be easier optics assembly.The equipment of design can be with
Back-to-back stacking.
Embodiment 13:For the exemplary electronic device used in preparation described herein and diagnostic device
There are multiple stand alone software components on specialized hardware:It is used in diagnosis (PCR) system described herein
The exemplary specification of electronic device.Other information description other places herein related with PCR system.In some embodiment party
In case, the PCR system includes nine kinds of different types of 18 printed circuit boards (PCB).About Figure 86, the system can be with
Containing there are three multiplexing (MUX) plate 100a-c, two of which (micro-heater MUX plate 100a-b) can be respectively for operation
Micro-heater plate 110a-b, and third (lysis heater MUX plate 100c) can run one or more lysis heaters
Plate 116 and 117.Each of three MUX plates 100a-c can be controlled via ethernet port PC processor plates.Two it is micro- plus
Hot device plate 110a-b heats the film micro area (microzone) on microfluid box respectively by a control of MUX plates 100a-b.
In some embodiments, the system comprises two lysis heater plates 116 and 117, are controlled by lysis heater MUX plates 100c
System, heat two 12 sample holders it is each in lysis pipe.
Still about the PCB being included in PCR system, the system may include two 12- channel optical detection plates
130a-b, can the optical fluorescence that is emitted by microfluid box chemistry of each self-test.Using SPI, on RS-422 interfaces,
It can be by one or more control optical detection plates of MUX plates 100a-c.The system may include three motor control panels
140a-c, one of plate (for example, motor control panel 140c) can control two Magnetic Isolation motor (not shown)s, and
And other two motor control panel (for example, motor control panel 140a-b) can one reader disk motor of each self-operating
(not shown) and a reader pressure motor (not shown).Run Magnetic Isolation motor motor control panel (for example,
Motor control panel 140c) it can be via the RS- from lysis heater MUX plates 100c and two motor control panel 140a-b
485 Interface Controllers, one reader disk motor of each self-operating and a reader pressure motor, can be via RS-485
Interface is controlled by micro-heater MUX plates 100a-b.System can also include a PC processor plate 150, instruct the system
The global weight of system, and can be via external ethernet and USB interface control and a PC processors base board 160, it will
The internal interface of PC processor plates 150 provides the rest part and external interface to system.The system may include a bottom
Plate (backplane) 180 is connected with each other whole system boards, a Motor Control bottom plate 190, by motor control panel
140a-c is interconnected to main bottom plate 180 and rack (not shown) and two door sensor plate (not shown)s.One door sensing
Device plate is locked in front door solenoid provides interconnection between PC processors base board 160, and another door sensor plate exists
Interconnection is provided between position sensor and PC processors base board 160.
In some embodiments, PCR system may include the PC processor plates 150 that can be purchased off the shelf.PC processor plates 150 can
To be board (ETX form factor board) in the form of ETX comprising a 10/100BASE-T ethernet port, four
USB port, a simulation VGA display port, two ports UART, a real-time clock, a parallel port, a PS2 key
Disk port, a PS2 mouse port, three-dimensional voice output, an ide interface and a 12C interface.
About Figure 87, the system can also include PC processors base board 160 comprising be used for five ends of intercommunication
Mouth 10/100BASE-T Ethernet bridges 161, one of them may be coupled to the 10/100BASE-T Ethernets of PC processor plates 150
Port, other in which can be used for diagnostic uses (having connector inside system covering), and three therein can
(each MUX plates 100a-c a ports) is communicated with three MUX plates 100a-c by bottom plate 180.PC processors base board 160
Can also include a USB for leading to 10/100BASE-T ethernet ports 162 for external ethernet connection, one is used for
Four port USB hubs 163 of external connection, an external VGA connector 164, an internal PS2 Genius mouses connector 165
(there are one connectors for tool inside system covering) and an internal PS2 keyboard connector 166 (have inside system covering
There is connector).PC processors base board 160 can also include an inside solid voice output 167 for leading to plate loud speaker 168,
One internal compression quick connector 169 (inside system covering have connector) from the ports IDE and one come from
The inside RS-232 interface 170 of the ports UART (there is connector inside system covering).It is included in PC processor base boards
In other element to may include an inside RS-485 interface 171 from the ports UART (have inside system covering
Connector), a internal temperature sensor 172 for being connected to 12C interfaces is used for the battery and a parallel port of real-time clock
173.About the connector having inside system covering, parallel port 173 internal can connect as follows:One control object
(bit) can be used for driving the solenoidal high current side switch of two doors, when any door sensor instruction door is opened, one
Control object can be used for generating processor interrupt signal, and three control objects can be used for programming EEPROM and be used for configuration ethernet bridge
161 and two control objects may be coupled to Ethernet bridge management interface (not shown).Remaining control object can keep unallocated
, resistor is pushed to and pushes with optional, and release to 10 needle Phoenix contact heads (header).
Referring now to Figure 88, in some embodiments, the system may include three MUX plates 100a-c.Although figure
88 describe exemplary MUX plates 100a, and each of three MUX plates 100a-c may include one or more spies as described below
Sign.MUX plates 100a may include 96 pulse width modulations for having heater (about 33 ohm to about 150 ohm) heater
(PWM) the heating channel controlled, can support 20 or 24 volts of (outside provide voltage) drivers, maximum current to be about
800mA.Each PWM can be the 12- bits for having programmable beginning and halt, can have 1 microsecond resolution ratio, and
It can be with about 75% maximum duty cycle.Each PWM cycle is programmable, and is preferably set to 4ms.MUX plates can
With the 4- conducting wire RTD/ heaters connection including precision 1mA sense currents, about 50 ohm to about 2500 ohm can be accommodated
Resistance Temperature Device and have +/- 0.5 ohm of accuracy of measurement.The thermal measurement sample cycle of MUX plates is 32ms, including 8
× PWM cycle, wherein respective 8 continuous passages of sample introduction of 12 16- bit A/Ds C101a.The addresses MUX can be tagged to ADC numbers
According to.
Referring still to MUX plates 100a, RS-422 the optics plate interface 102a described in Figure 88, on bottom plate 180 mutually
Connect and exchange signal in 4 conducting wire SPI interface transmitting datas using local synchronization, and interrupt signal may include
On MUX plates 100a.MUX plates 100a can also include 10/100BASE-T Ethernet interface 103a, be interconnected to bottom plate 180
On system and RS-485 interface 104a, the motor controller 140a being interconnected on bottom plate 180.
Referring now to Figure 89, in some embodiments, the system may include optical detection plate 130a-b.Although figure
89 describe exemplary optical detection plate 130a, but each of optical detection plate 130a-b may include one or more as follows
The feature.Optical detection plate 130a may include being modified as designing using the 12- channel optical plates of RS-422 interfaces 131a.
Optical detection plate 130a may include the blue led 132a drivers at 12-3 watts of about 625mA maximum values about 6V
(driven).The exemplary LED used in detection plate 130a is the Luxeon K2 transmitters for the blue light for generating about 470nm wavelength,
It uses about 27mW@700mA.Optical detection plate 130a can also be included in 12-3 watts of about 625mA maximum values about 6V, amber
Color LED133a drivers.The exemplary LED used in detection plate 130a is the amber light for generating about 590nm wavelength
Luxeon K2 transmitters use about 60mW@700mA.Detection plate 130a may include the silicon photodiode detector of 24 lens
134a, one of embodiment are Hamamatsu S2386-18L.These photodiode detectors 134a is designed in commonly
TO-18 packaging in.Detection plate 130a can also include the MSP430 processors 135a having there are two the channels PWM, and one is used for
Blue channel and one are used for amber chrominance channel.Plate 130a may include individual LED, can be used in 12 colors pair
The 136a and 137a of each are arranged on local spi bus.
PCR system may include lysis heater plates, provides and monitors the heating for lysis pipe.Heater plates can
To include 12-70 watts of TO-247 power resistor (providing heat to lysis pipe), be designed to from MUX plates 100a-c (for example,
MUX plate 100c) one or more and 12-2000 Ohmic resistances temperature device (RTD) power 24V to monitor the lysis pipe
Temperature.May include optional resistor to change the complete meter full scale of RTD.Include on lysis heater plates be series connection
EEPROM with accommodates plate serial number and can be used to identify board type and for the revision level of software.
Referring now to Figure 90, in some embodiments, the system may include micro-heater plate 110a-b.Although figure
90 describe exemplary micro-heater plate 110a, and each of micro-heater plate 110a-b may include one or more as described below
Feature.In some embodiments, the system may include micro-heater plate 110a comprising concatenated EEPROM and two
A optics cutout.Series connection EEPROM can accommodate RTD calibration data, and can be used to identify plate class with accommodates plate serial number
Type and revision level for software.Optics cutout can be used for sensing the reader disk position of motor control panel 140a, and
And Blue Cobra (motor controller) are will send information to, the information on processing reader disk position, and therefore control
System is led to by the power of the motor control panel 140a transmitters powered.It is micro- that micro-heater plate 110a may provide for 96 channels
The connection of heater plates, and 96 multiplexing heaters/RTD device is controlled with control box characteristic temperature.Heater/RTD dresses
It sets and can be arrived between about 500 ohm at about 50 ohm.Micro-heater plate 110a can be by RS-422 interfaces from for example, MUX plates
100a is bridged to optical detection plate 130a.Being connected to MUX plates 100a from micro-heater plate 110a and is connected on bottom plate 180
It is on 40 needle FFC cables to optical sheet 130a.
Referring now to Figure 91, in some embodiments, the system may include motor control panel 140a-c.Although
Figure 91 describes exemplary motor control panel 140a, motor control panel 140a-c each may include it is one or more such as
The lower feature.In some embodiments, the system may include motor control panel 140a, can control two
Micro-stepping motor 141a, and bottom plate 180 can be connected to via RS-485 interfaces.The output of motor can be up to
24V, this is being externally supplied by bottom plate 180.Output current can be that jumper is selectable.It can be set via jumper
The exemplary output current for setting selection may include about 700mA, about 1.0A or 2.3A.Motor control panel 140a includes leading to
The opening collector TTL interrupt outputs of MUX plates 100a and mark input.Mark input can provide 1.5V power outputs to biography
Sensor and can be by software switch.
Limit switch is placed on the final position of respective axis, for example, x- minimum values and x- maximum values, send out in failure
The power supply for leading to the motor for driving the axis is closed in the case of life, and head of pipette is removed from design work distance.
It is optional that push to and push used for the output of optics cutout.)
In some embodiments, the system may include one or more interconnection plates, such as main bottom plate
180.Main bottom plate 180 can be connected with each other other PCB, such as MUX plates 100a-c, PC processors base board 160, and add
Hot device is connected with each other plate.Motor Control bottom plate 190 can be connected to cable for main bottom plate 180 and cable is connected to two lysis heaters
Plate.Main bottom plate 180 can on bottom plate 180 distribution power and signal, realize 10/100BASE-T Ethernets and RS-485, and
And supply voltage from aerial lug.Exemplary voltage is supplied including+3.3V ,+5.0V ,+12.0V, -12.0V ,+20.0V, and+
24.0V。
System may include Motor Control bottom plate 190, can be used for whole Motor Controls with distribution power and signal
Plate 140a-c.Motor Control bottom plate 190 can be from aerial lug supply+5.0V and 24.0V.Motor Control bottom plate 190
It may include 1 slot (amounting to 2 slots) used in the RS-485 signal transductions of each from two MUX plates 100a-b, come
6 slots used in RS-485 signal transductions from the lysis heater of control MUX plates 100c, and by RS-485 signal transductions and work(
Rate provides a connector to rack.Motor Control bottom plate 190, which can provide, pushes to and pushes resistor to operate floating-point
Data/address bus.
In some embodiments, the system may include that heater is connected with each other plate and door sensor plate.It is used only
Physics is connected with each other (for example, without movable circuit), and heater is connected with each other plate can be by the 110a-b connections of micro-heater plate
To main bottom plate 180.Door sensor plate can provide cable interface and the mixed logic from optics cutout, described in sensing
Door is opened, and provides installation and stranding interface to door locking solenoid.
Embodiment 14:For the exemplary software used in preparation described herein and diagnostic device
In the presence of the multiple stand alone software components run on specialized hardware:
Reader (2);
Sample-preparation (1);
User interface (1);
Detector (2);
Motor Control (8)
Communication is via internal Ethernet data bus between component wherein, and the communication with user interface is via height
Fast SPI data/address bus and be via the serial portion's lines of RS485 with the communication of Motor Control.
Reader and sample preparation running software in same hardware, and thus in the same manner combine following function:
Wscript.exe (script engine) (parametric form of regulation)
Regulation tool (protocol engine)
Temperature control (microfluid, lysis, release)
Motor Control (via exterior motor control member).Motor control software is noteworthy characterized by:
Order/reply and addressing performance in ASCII is to allow the data collection and clearing system (daisy) of communication connection
Link.
Detect (via external detector component) detector component control LED illumination and photodetector digitlization.
The program that user interface is embodied as running under a linux operating system on embedding x86 compatibilities PC.It solves
Following function:
The user interface of diagram
Testing and control and monitoring
Test result storage via Ethernet (arriving laboratory information system) and retrieval network connectivity
USB interface
Printer
Scanner (inner and outer)
Keyboard
Genius mouse
Door locking and sensing
Embodiment 15:Exemplary chemical method and application method
Chemical method is summarized:
Chemical method surrounds biological detection and identification in clinical sample, by means of from the biological detection nucleic acid.This
It is related to the target bio-separation nucleic acid from included in clinical sample, followed by method existing for specific nucleic acid sequence will be detected.It removes
Except target detection, internal positive control nucleic acid will be added to collection buffer solution, and will be in all extraction and detection process
It is used with together with target nucleic acid.The control will monitor the efficiency of all processes, and will make to have the risk of false negative result most
Smallization.
Nucleic acid extraction and purifying:
Nucleic acid extraction step, which starts from clinical sample being added to, prepares sample collection solution.This can be in sample collection position
It sets or is carried out in test position.It will be obtainable that two, which are collected solution form,:One is used for body fluid, and one is used for swab
Sample.Sample transport solution is will act as collecting the collection solution that position uses, therefore, which must keep sample and analysis
Object integrality.
The extraction of full automation and purifying procedure carry out as follows:
By target biology by heating the collection solution lysis containing detergent.
The magnetic beads for being added to sample/collection solution mixture non-specifically combine all DNA being discharged into solution.
Magnetic beads are detached and are washed to remove pollutant
Using high pH and heat from the pearl released dna.
Solution containing DNA is removed and is neutralized with buffer solution.
Nucleic acid amplification:
It collected by magnetic beads, washing, discharge in high pH and be added to buffering with the nucleic acid of sum in buffer solution
In the mixture of liquid, salt and the enzyme being lyophilized in pipe.By mixture rapid rehydration, then a part for solution is filled
It is downloaded on microfluid box.Then by it is described it is box-packed be downloaded in amplification instrument component, by can thermal cycle heating equipment and light
Learn detecting system composition.The detection of target nucleic acid carries out as follows:
The liquid of sealing in the reaction chamber.
By rapid thermal cycles for reinforcing PCR (PCR), use it for expanding specific target DNA.
The DNA of amplification fluoresces, and can be detected with optical sensor.
Fluorescence probe " tail " is attached in the DNA fragmentation of each amplification
In actual temp, the probe is using the conformation for generating fluorescence (this is known as " scorpion " reaction, sees Figure 84).
Fluorescence is detected and monitored in total overall reaction.
Extraction and amplification/detection method:
Extensive experimental bench scale test has been carried out to optimize nucleic acid extraction chemistry, including collects buffer solution, washing
Buffer formulation, release solution preparation and PCR reagent mixture.The extracting method of full automation, it is upward followed by 12-
PCR can be provided consistently in 150 copies/sample very highly sensitive.
Embodiment:Chlamydia (50/50) in urine;Gonorrhoea in urine;GBS in blood plasma.
Multiple detection chemistries such as Taqman, Scorpion, SYBRg the Green reliably work in microfluid box
Make.
Reagent manufactures
Feasibility study is carried out, to determine whether PCR reagent can be in PCR pipe in addition to using 2 μ l freeze-drying beads
Freeze-drying.Research is it has been shown that the sensitivity of the reaction carried out using pipe freeze-dried reagent is equal to the spirit of wet reagent or the 2 small ball agents of μ l
Sensitivity, so verified feasibility.The stability study of the form shows similar stability data.The present inventor has seen
To once being sealed in nitrogen atmosphere, 2 microlitres of freeze-drying PCR beads are stablized up to 2 years at room temperature.
Manufacture summary:Manufacture system element can be in HandyLab companies, Ann Arbor, MI realizations.Manufacture is appointed
Business is divided into five regions consisting of the following:Chemistry manufacture, disposable item collect kit, box and analyzer.
Chemistry manufacture:The chemical composition being individually blended presently, there are seven is accredited as with for system described herein
System potentiality used.Mixing, mixes and reagent treatment/chemicals can be carried out in HandyLab companies, and existing equipment exists
Appropriate location.Other tool and fixed equipment will be necessary, because product is ripe, and the present inventor is expanded to high volume
Production, but initial cost will be minimum.
Buffer solution is collected, washing, release and neutralising fluid are the straightforward procedures for having extremely low risk, and can be big
It is manufactured in batch to keep the labour cost of mixing/mixing to be equal to or less than target design.They will be mixed and are placed on
For in the intermediate receptacle of storage, be then out (issue) for distribution disposable item manufacture.Ripe SOP is in next
From the position of existing scheme behavior.
Affine pearl (AB) has the good potentiality for being stored and being used as liquid in the item, but for using freeze-drying small
The design contingency sum of ball is in as on the position of standby.During distribution, it is important that keep suspending by the pearl
In the solution.Once demonstrating stability for the liquid A B storages in the item, continuous suspend is provided during distribution
The distributing equipment (for example, being manufactured by Innovadyne) of the agitation of liquid has been identified as buying.Manufacture and magnetize affine pearl
Method crosses over 9 hour circulation time to generate the batch of 2,000 aliquot, once but the present inventor is expanded into high volume
Production, then the phase same time can be used for amplification method batch.The project is for described device all chemistry systems required at present
There is highest workload in making.
PCR reagent/enzyme will be lyophilized in the existing cryodesiccation chamber of the present inventor (Virtis Genesis), but will not
Spherical granule is needed to be formed.Instead, mixture is being assigned to inside final use pipe, then inside final use pipe
Freeze-drying.First, the chemical substance (chemistry) is mixed according to determining SOP, then carries out the following steps and is frozen with realizing
Dry method:Independent pipe is put into holder/fixed equipment, and is assigned to solution often using existing equipment (EFD excessive distribution station)
In one.The holder of filling will be placed on stainless steel pressure box (being modified as receiving plug in the lid) inside, then place
Into cryodesiccation chamber, and start arid cycle automatically.During freeze-drying, plug allows air/nitrogen circulation in raised position
Into and moisture leave keep vial carrier stainless steel case.At the end of cycle, the cryodesiccation chamber frame of the present inventor reduce so that
The plug is placed in lid, sealing is formed, while still inside sealing chamber, in the nitrogen atmosphere of no moisture.Then from
The room removes steel case, and internal each holder should process in a procedure so as to described in being sealed in whole bottles
On holder.And then after sealing, bottle will be punched from the foil in one operation, and individual bottle is allowed to reach forward
To disposable fabrication region, for being put into an item.Internal contrast will be added into existing solution, or will be to collect
Buffer solution, washing, neutralization and release solution mode be assigned in the cavity of own.If necessary to be lyophilized, it will use and
Method as PCR chemistry is realized, and is then moved quickly into the item.Shelf life stability research is to carry out
's.
Collect kit manufacture
Initial number will be reached in internal artificial by collecting kit.Initial number not may require that capital cost, because
The present inventor has required armamentarium so that the present inventor meets the design by 2008.The present inventor will use its existing
Equipment (EFD 754-SS aseptic valves and Valvemate7000 digitial controllers) is to fill collection vial.The bottle has
Distortion on top will be torsion, and the bottle will have proprietary ID bar codes on each bottle.24 bottles
It will be placed in the polybag that can re-cover tightly, and be placed into the carton for transport.
Bottle is put into holder.
Solution is assigned in bottle.
It installs and reverses lid.
Mark bottle.
Bottle is packed and marks bag.
Bottle bag and specification/insert are put into carton, closes and marks.
Box manufactures:
Existing semiautomatic equipment (the Think&Tinker DF-4200 , &Asymtek Axiom for being laminated and waxing
Heating injection platform, respectively) it will be used to meet whole box manufacture requirements.The area of coverage of the upward disposables of 12-
(footprint) identical as RTa10 boxes, so in addition fixed equipment is not required.
The micro- base of laminated material and finishing are excessive.
Valve and inspection are filled with hot wax
Apply label and bar code.
24 are combined together.
The box of bag and sealing winding, marks bag.
Bag and insert are placed in carton, sealing and label.
This portioned product is relatively simple, although automation (as used herein) and Dan Li the upward boxes of 12- it
Between difference.It not may require that floss hole on the box, eliminate the most time-consuming process for box manufacture, and for complete
The highest risk and tip heigh of integrated automation.In on piece upward 1,000 12- with floss hole by success real estate
It is raw.
Embodiment 16:Exemplary chemical method
Sample pretreatment
For urine samples:The urine of 0.5ml is taken, and it is collected into buffer solution with the HandyLab of 0.5ml and is mixed.Pass through
HandyLab companies prefilter (containing there are two the films of 10 microns and 3 micron pore size sizes) filtered sample.Sample cell is placed
In for the specified position of external sample pipes of the 12- into upper bracket.
For plasma sample:0.5ml blood plasma is taken, and it is collected into buffer solution with the HandyLab of 0.5ml and is mixed.By sample
Quality control is placed in the specified position of the external sample pipe for 12- into upper bracket.
For GBS swab samples:It takes swab samples and it is immersed in 1mlHandyLab and collect in buffer solution.By sample
Pipe is placed in the specified position of the external sample pipe for 12- into upper bracket.
HandyLab sample collection buffer solutions contain 50mM Tris pH7,1%TritonX-100,20mM citrates,
20mM borates, 100mM EDTA, in addition the positive control dna of 1000 copies.
It loads the instrument and starts sample treatment
1. the PCR pipe containing PCR Master Mix to be loaded in one of the specified snap-on position of combination disposable
In.
2. the PCR pipe of target analyte primer containing PCR probes and under study for action is loaded in combination disposable
In designated position.
3. in the case of two analyte testings, the PCR pipe of the primer containing probe and for the second analyte is filled
It is loaded in the designated position of combination disposable.
4. being loaded in combination disposables of the 12- into upper bracket in channel identical with the sample cell in research.
5. preparing and loading other samples during composite reagent item is used to study.
6. 12- is loaded in upper bracket in one of position in instrument.
7. 12- box-packed is loaded in the box disk " loaded " position upwards.
8. starting to operate.
Liquid processing steps
1. using pipette tip #1, clinical sample is transmitted to a group unification by the automation from the external sample pipe
In the lysis pipe of secondary property item.
2. using identical pipette tip, automation takes the sample of about 100 μ l, freeze-dried mixed enzyme and affine pearl, will
Reagent is transmitted to lysis pipe.By 5 absorptions and batch operation, mixed in lysis pipe.
3. pipette tip #1 is placed on it in the designated position in combining disposable item by automation.
4. lysis pipe is heated to 60C and keeps it 10 minutes.
5. after 5 minutes lysis, automation picks up pipette tip #1 and is drawn by 3 mixed with batch operation
Co content object.
6. pipette tip #1 is placed on it in the designated position in combining disposable item by automation.
7. after 10 minutes lysis, magnet is moved upwards up to the center height of sample in the side of lysis pipe, and
And kept for 1 minute in the position to collect whole magnetic beads against tube wall.
It is slided close to the bottom (rather than bottom) of pipe with the pearl that will be collected 8. slowly reducing magnet.
9. using pipette tip #2, extracting whole liquid out and it being poured into waste pipe.
10. second of extraction from lysis pipe to remove liquid as much as possible.
11. using identical pipette tip #2, withdrawing the washing buffer of 100ul and distributing it in lysis pipe
In.During the distribution, magnet is moved down, far from lysis pipe.
12. executing 15 mixing steps thoroughly to mix magnetic beads with washing buffer.
13. waiting for 30 seconds.
14. magnet is moved up, the pearl is collected into side and is kept for 15 seconds.
15. using pipette tip #2, washing buffer is extracted out twice to remove liquid as much as possible and it inclines
It refunds in sluicing pipe.
16. magnet is moved down away from lysis pipe.
17. pipette tip #2 is placed on it in the designated position for combining disposable item.
18. picking up new pipette tip (suction nozzle #3) and withdrawing 8-10 μ l release buffer solutions and distribute it molten
On pearl in born of the same parents' pipe.
19. waiting for 1 minute then to execute 45 mixing.
20. release solution is heated to 85 DEG C and keeps temperature 5 minutes.
21. pipette tip #3 is placed on it in the designated position for combining disposable item.
22. keep magnet upward along the pipe, against tube wall collects whole pearls and move up it and far from pipe
Bottom.
23. picking up new pipette tip (suction nozzle #4) and withdrawing all release buffer solutions from lysis pipe, then withdraw
It is mixed in pipette tip and distributes it in PCR pipe by the neutralization buffer of 3-10 μ l.(in two analytes
In the case of detection, the half of the DNA solution of neutralization is assigned in the first PCR pipe, and the rest part of solution is distributed
In the second PCR pipe.
24. using pipette tip #4, is drawn by 4-5 times and batch operation mixes the DNA of neutralization with freeze-dried reagent
And withdraw the complete soln in pipette tip.
25. pipette tip #4 is used, by the final PCR solution stowages of 6 μ l in the channel of the upward boxes of 12-.
It is illustrated schematically in Figure 85 A-C in the use of the head of pipette during multiple methods.
Real-time PCR
After the final PCR solution stowages in all appropriate channels PCR of PCR boxes, the disk containing the box is by it in PCR
It is moved in analyzer.With optical detection read head against PCR heater joint boxes.Heater-driven valve closes PCR reactors
Either end, and start real-time Thermal Cycling.After completing PCR cycle appropriate (~45 cycles), based on output
Fluorescence data, analyzer generate sample whether the signal with target DNA.
Pipette detects
Head of pipette has 4 infrared sensors, the presence for detecting pipette.This is for ensuring computer accurately
Know that pipette is to exist or lose to be important.Because pipette is picked up using mechanical force against pipette, and use
The mechanical movement of stripper plate distributes, so pipette sensing helps prevent the failure that can in addition occur.
The power of head of pipette senses
More heads of pipette, and the force snesor with its interface are assembled in such a way, so as at any time, liquid relief
Tube head is placed against disposable pipette, or the pipette selected is forced past the lamination material in reagent disposable
Material, or force pipette against the bottom of reagent disposable middle pipe, nozzle or pipette itself are kept by pipette, to
On force effect on head of pipette.Whole heads are rotations, and as shown in the figure, and any power acted on the head is drawn
The fixing screws for playing the head top squeeze force sensor.This is calibrated about the head vertical displacement for non-moving surface
Force snesor.Use this calibration, it may be determined that when stop the mobile head in the z-direction, whether to detect pipette
Whether appropriate placement or pipette reach bottom of the tube.
Pipette tip is harmonized, while PCR reagent being loaded into microfluid box.
The pipette used in device can have small to 10 μ l to greatly to the volume of 1ml.Larger volume pipette can be with
It is to be up to 95mm (p1000 pipettes).When 4 long pipette tips are bounced from the head, even if 1 ° of dislocation during placement
Suction nozzle can also be made to deviate center 1.7mm.Because can not possibly be with complete at the top that it has a common boundary with suction nozzle fixator and bottom
Suction nozzle harmonize, it is therefore necessary to by whole suction nozzle mechanical restrictions in another position closer to bottom.The present inventor is
Through having used stripper plate, there is the pore structure limited, to use it to harmonize whole suction nozzles.When they are picked, stripping
It clears all 4 pipette tips from device plate hole.After suction nozzle is suitably placed, stripper is moved in x- axis using motor
Plate, so as to the whole pipettes of recess movement provided in opposite stripper plate (referring to Figure 25 B).Now, whole pipettes are easy
Ground reaches box ingate.
Sample preparation extends
The details of the processing clinical sample of the technology of the present invention description extraction polynucleotides (DNA/RNA).It is magnetic by changing
Affinity molecule present in pearl, like products platform can extend to processing sample to extract protein and other macromoleculars.Expand
Increasing-detection platform can be also used for executing other enzyme reactions, such as immuno-PCR, reverse transcriptase PCR, TMA, SDA, NASBA,
LAMP, LCR, sequencing reaction etc..Sample preparation can be also used for preparing the sample of height multiplexing microarray detection.
Embodiment 16:Exemplary materials for RNA- affinity matrix
Exemplary polynucleotides collection material preferentially keeps more when contacting placement with fluid nutrient medium on its surface
Nucleotide such as RNA, the fluid nutrient medium contain the polynucleotides mixed with other types such as protein and peptide, it is described its
Its type can inhibit the detection or amplification of subsequent polynucleotides.
Exemplary polynucleotides collection material is:It 0 generation of polyamidoamine (PAMAM), can be from Sigma-Aldrich
Chemical Company (Sigma-Aldrich chemical company) (" Sigma-Aldrich ") are obtained, production number
412368.PAMAM is dendrimer, and molecule contains the mixture of primary amine and tertiary amine group.PAMAM (0 generation) has herein
Shown in structure.
During use, PAMAM is fixed on solid carrier such as carboxylation pearl or magnetic beads.It collects and grasps in polynucleotides
During work, polynucleotides collection material includes polycation molecules.Compatibility between material and polynucleotides be it is high, because
Include usually polyanion in the solution for polynucleotides such as DNA and RNA.
Remaining inhibitor and other compounds in polynucleotide molecule collection on material surface, and in solution are
With alkaline buffer solution after such as 0.1mM Tris (pH8.0) aqueous solution rinses out, the polynucleotides can be with itself from material
Expect surface release, this washs the material by, for example, the Tris for being 9.0 with the second more alkaline buffer solution such as pH and carries out.
It finds to use in nucleic acid test in the U.S. patent application serial number 12/172,214 that on July 11st, 2008 proposes
The exemplary regulation of PAMAM, is incorporated herein by reference.
Embodiment 17:Exemplary materials for DNA- compatibility matrixes
Exemplary polynucleotides collection material is:Polyethyleneimine (PEI), can be from Sigma-Aldrich chemicals
Company (" Sigma-Aldrich ") obtains, production number 408719.
It finds to use in nucleic acid test in the U.S. patent application serial number 12/172,208 that on July 11st, 2008 proposes
The exemplary regulation of PEI, is incorporated herein by reference.
Embodiment 18:Exemplary device
Described herein is the exemplary specification of the Machine Design for PCR system.In some embodiments, described
System can be about 28.5 inches of depths or less and about 43 inches wide or less, and weigh about 250 pounds or less.The system can
To be designed with about 5 years service life (for example it is assumed that annual 16,000 test) and can be designed in this way, so as to the instrument
The sound levels (during operation) of device are no more than 50dB when on whole coordinate directions apart from 12 inches of measurements of instrument.At some
In embodiment, the outside of system can be white, have texture.
In some embodiments, about overall system, the decisive element of system can keep orthogonal or parallel and (drink
Feelings) in 0.04 degree.Exemplary decisive element may include tracks, and pipette, nozzle is (for example, axially make
For single nozzles, the linearly array as four nozzle barycenter, etc.), lysis heater, the box installed in reader pull tool
The major side of fixator, before separation magnet, etc..In the description which follows, X- axis (or X-direction) is referred to when the system of facing
The axis extended from left to right when front, Y- axis (or Y-direction) refer to the axis extended from back to front when in face of system front, and
And Z- axis (or Z-direction) refers to the axis extended upwardly from the bottom portion when in face of system front.From coming from instrument tip, Z- has
The barycenter (from coming from instrument front) for most moving to left liquid pipe nozzle imitated in load can be in X-direction from apart from outermost left base
The position of plinth edges of boards edge 80mm is accessible to be moved to apart from the outermost left base plate edge positions 608mm, and can be in the side Y
To from being moved to apart from the position of outermost preceding base plate edge 410mm apart from the position of outermost preceding base plate edge 60mm is accessible
It sets.
Still about the system, from coming from instrument front, the bottommost face of the pipette nozzle in Z- payload
It can be moved to the above 256mm's of basic plate top surface from the position of the above 156mm of basic plate top surface is accessible in the Y direction
Position.1ml pipette tips can be penetrated including the foil covering on disposable reagent strip.This, which is penetrated, to generate
Pollution influences related chemistry, or destroys pipette tip.As needed, can execute in such a way movement so as to
Remove mechanical hysteresis effect.Stage motion can be optimized to prevent cross aisle from polluting and migrating (carryover).Holder can be with
Reagent strip is registered to +/- 0.010 inch of tolerance on X and Y-direction.
Now concerning the rack, in some embodiments, what the rack can be driven by stepping motor, band/
The cartesian automatic mechanical system of screw drive forms.The rack can move freely more than component, with and without even
Connect, if the component in the rear bottommost horizontal plane just forward and on Z heads hereinafter, Z- payload is fully retracted.
Rack movement speed can be up to about 500mm/ seconds in x and y direction, be up to about in z-direction 100mm/ seconds.Axis moves
Accuracy and precision (for example, relative to X, Y and Z internal sensors) can be 25mm for each axis or more preferable, and
It may remain in whole maintenance periods.Axis driving band can not leave residue in the region of processing PCR and sample.It is described
Rack, which can contain, to be useful for own and whole Z- payload bunch selecting the device that route returns to instrument.On X and Y-axis
Band tension can be arranged at 41.5+/- 3.5 pounds.
Now concerning Z- payload, fluid head can have 4 to be located at the supercentral pipette connection nozzles of 24mm.
In the case of non-leakage, the exemplary pipette tip that pipette nozzle can be collected includes Biorobotix suction nozzles
PN23500048 (50 μ L), PN23500049 (1.75 μ L) and PN23500046 (1ml).Z payload can be combined and can be removed
The stepper drive stripper plate of pipette tip (for example, pipette tip described above).The system may include pump and
Manifold system comprising the extraction of the software control of the independent fluid volume within each of four independent suction nozzles, distribution,
And it distributes and discharges while in discharge, and whole suction nozzles.Pump and manifold system can have the volume less than 20 μ L
There are the volume accuracy and precision of about +/- 2 μ L/ suction nozzles, and has about +/- 10% for the volume more than or equal to 20 μ L
Volume accuracy and precision (for example, when in independent suction nozzle extract out or distribute when).Master cylinder stroke volume can be greater than about 8
μ L and be less than about 1250 μ L.Minimum extraction and dispensing rate can be about 10 μ L/ seconds to about 300 μ L/ seconds.Each pipette is inhaled
The barycenter of the most bottom surface of head can be with the nozzle face heart axial alignment of pipette nozzle within 0.2mm.Bottommost pipette is inhaled
Head can be coplanar within 0.2mm.Z- payload can be in conjunction with Z axis force snesor, can be by about 0 to 4 pound
Applied force feed back to software.Z- payload can be read in conjunction with the bar code reader faced downwards as herein
The system bar code of other place descriptions.
Now concerning including holder in systems, disposable reagent strip (for example, being oriented orthogonally to the front of instrument) can
To be included in 2,12- channel brackets.It can be automatically recorded simultaneously when being inserted by user to 12 reagent strips in fixed rack
It is locked in holder.Holder, which can contain, to be useful for 12 sample lysis pipes (for example, PN23500043) and keeps the tube bottom
The coplanar region in portion allows user to orient bar code in face of the back side of instrument.Certain features, including it is listed above
Those, can allow the holder to be inserted by minimum trained user and be oriented in the instrument.It can be by feeding back to
Software confirms that holder appropriate is placed.In some embodiments, the holder can be (the example of black and color fast
Such as, using or in the case of washed with 10% liquid lime chloride, color can not be reduced slightly) and timbering material can be
Spatial stability is within 0.1mm on the operating temperature range of system.The holder can be designed with allow holder can be transported to and
From the instrument and the devices of following possibilities is reduced or eliminated, the possibility is, when placing in the plane, to be propped up
The pipe that frame is kept will overflow.
Now concerning including in systems reader and PCR heaters, the reader can be inserted into order to box minimum
Trained user simultaneously therefrom removes.Box can keep being placed in reader during system operatio.In some embodiments
In, if compartmentalized box for holding assorted fruits and candies is inserted into incorrect (for example, reverse or backward), box bar code can not suitably be read by barcode scanner,
Thus when box insertion is incorrect, system can indicate that the box is correctly inserted into reader disk by user.It reads
Device pull tool can position the box repeatedly, for being loaded within 0.5mm with pipette tip.Reader can will come from
The box of " loaded " position is delivered in reaction and test position, this by means of software control under automatic pull-out mechanism.The box
The channels PCR can be aligned with both optical system and heater with reader disk and pull-out mechanism.The box can be used about
1psi or the average pressure of the bigger uniform contact heater in the channels PCR and the region of wax valve.Heater can be protected to lead
Line is connected from being destroyed, and is moved so as not to interference system.It can to the record at optical path center from heater to box and from box
With within +/- 0.010 inch.Reader can a minimum of about 80,000 times movements of mechanical cycles in the case where not failing.
Now concerning being included in one or more of system lysis heater, for 24 lysis stations each plus
Hot device can be that stand alone software controls.Lysis ramps the time (for example, the temperature of water in lysis pipe from about 2.5 DEG C
It is increased to given temperature the time it takes) it can be less than 120 seconds for rising to 50 DEG C, it can be less than for rising to 75 DEG C
300 seconds.Lysis temperature (for example, being measured in the water for such as including in lysis pipe) can be maintained at required temperature with lysis heater
In +/- 3 DEG C of degree.Accessible lysis temperature range can be from about 40 DEG C to about 82 DEG C.Each of lysis heater exists
About 16 watts or more of power can be obtained when in operation.Lysis heater can be designed to make the heat transfer of arrival lysis pipe maximum
Change, and is also adapted to the tolerance of the part.Lysis heater can allow lysis pipe to be in direct contact (herein more in detail with magnet
It carefully describes).The lysis heater period of assembly can be on horizontal plane it is adjustable, and installation can not be interfered
System covering.
Now concerning including magnet in systems, lysis and magnet associated mechanisms may be mounted under holder and can
Not interfere holder to be inserted into or record.Magnet can be that high-strength force flow magnet (for example, when being measured in given lysis pipe, has
Have the flux of about 1,000 Gausses or more) and can move and be enough to realize one or more lysis pipes for being filled into 900 μ L volumes
In magnetic beads separation distance.The magnet can control the rate travel at about 1mm/ seconds to about 25mm seconds with software.Wiring,
Include the part for heater and controller assemblies, can by comprising and prevent potentially overflow (for example, lysis pipe overflow
Go out).Magnet can be positioned at when not in use apart from about 1.25 inches of lysis bottom of the tube or more, and can be with such a
Mode keeps maximizing so as to the contact with lysis pipe, while being also prevented from interference.
In some embodiments, the system shell includes translucent cover (for example, with opaque in instrument front
Fixing device and/or hardware) to allow user to watch instrumental function.Lid may include company and/or product identification and can grab
Handle (for example, user is made to improve the lid) firmly.Upon closing, the lid can have the opening force (example no more than 15 pounds
Such as, when handle base edge center tangent line measures rotation), and unlatching (for example, " upward ") position can be locked in
It sets, to need at most about 5 pounds of power (for example, be applied to handle and be tangential to a rotation) to overcome handle locking and incite somebody to action
The lid returns to closed position.The lid may include two safety head lockings, and when not applying power, it is usually locked out
, and allow the state (for example, being turned on and off) of the system monitoring lid.The lid can be designed in this way, working as
The lid is not fallen when between opening and closing position.The shell may include the power switch in the right positioner of instrument.
Power cord can in such a way from the shell stretch out, the mode be position the instrument do not destroy the line or
Cause unexpectedly to disconnect.Shell can prevent user and such as moving component, highfield, effective electrical connection etc. from being connect
It touches.Shell may include four support foots, be located in the downside of shell, to provide about 0.75 English between table top on the downside of shell
Very little or more gap.Shell may include leading to external attached connection such as display port, ethernet port, the ports 4USB
Deng recessed area.
Now concerning the cooling subsystem being included in PCR system, air inlet can be provided in equipment front, and air
Discharge can be provided in the rear portion at the top of equipment.Intake air can pass through air inlet and by filter cell (for example, can
Mobile and washable filter cell).Cooling subsystem can keep Inside Air Temperature (for example, reagent strip such as
The surface of reagent strip number 1,12 and 24, in the temperature of the measurements such as PCR boxes surface) at 10 DEG C about higher than ambient air temperature or
Less.Cooling subsystem can keep Inside Air Temperature to be equal to or less than about 32 DEG C.Part packet as cooling subsystem
The one or more cooling fans included can need about 5.7 watts or less power/fan.
In some embodiments, the system may include the covering on mounted inside part (in addition to rack).It covers
10% liquid lime chloride that cover material can be applied with soft cloth cleans, without significantly degrading.Covering user and can be included in
The offer safety barrier between the mechanical component of movement of electronics in the system.Covering on mounted inside part can be with
It is designed to, by making the air-flow under covering maximize and making the minimum gas flow on covering, and makes mounted inside part
It is cooling to maximize.Covering can be moved by Service Technicians, and can be with the color and quality of matching can.
In some embodiments, the system can be designed within the temperature range of about 15 DEG C to about 30 DEG C and non-
RH range (for example, relative humidity of about 15% to about 80%) is condensed to run.Analyzer can be designed in exposure
It in not less than -20 DEG C storages 24 hours or less, is being stored 24 hours no more than 60 DEG C or less, and/or about 50,
000 foot or less (for example, 3.4 inches of Hg) store 24 hours or less it is later do not damage in the case of run.System can be with
The device for having and preventing movement is designed, the movement may destroy the instrument during transportation.It can meet ASTM
The transport standard stated in D4169-05, DC 12, and can be designed to that base plate is allowed to be reliably mounted to transport goods
Disk.By the holder of instrument and shelling machine at not degraded or damaged with the cleaning of 10% liquid lime chloride daily.Lead to system
The power supply of assembly parts can be supplied by internal electric source.Exemplary power supply can arrive about 264Vac about 90, in about 47 peace treaties
Between 63Hz, receive about 1590 watts as input, and about 1250 watts of output is supplied to assembly parts.
In some embodiments, the system may include power switch (for example, rocking bar-type of switch), be located at instrument
On the right side of device, one or more interface elements, and/or one or more interface ports.For example, the system may include LCD aobvious
Show monitor, be 15 inches, there are 1280 × 1024 pixel resolutions and 16- colors.The system can also include it
Its display monitor, such as with increased size, the display monitor of resolution ratio and/or color depth.It is connected via VGA, it can
LCD display is connected to the system.System may include 2 button USB mouse devices of white, white USB keyboard, black
SJT feed cables and continual power supply, are fed back by USB.System can also include USB color printers, 2 USB cables
(for example, one is used for printer, one is used for UPS).System may include exemplary interface port, such as, 4 USB ports
(for example, being connected to pointing device, printer, keyboard, UPS, LIS), 1 VGA port for being connected to LCD (for example, show
Device) and 1 ethernet port (for example, being used for PC connectivity), it is located on the left side of shell.IEC/EN 60320-11C14 electricity
Source port may include in the right side of shell.
In some embodiments, it is to increase the feature of user's safety that the system, which may include purpose,.For example, can
To include door interlock to prevent user from accessing during exercise and/or when non-interruption process carries out in rack.System
The presence of the come-at-able dangerous corner of user and/or edge on instrument can be designed to reduce or eliminate, and be designed to
In this way, so that metal parts is correctly electrically grounded.Can include that sheet metal or plastics cover on mechanically and electrically element as needed
Object is protected with protecting the user from moving component and/or effective electronic unit including electronic device in systems
It avoids with motor, for example, falling.
Embodiment 19:Exemplary optics
Described herein is exemplary specification related with the optical design used in PCR analyzers and/or system.With
The related other information description other places herein of PCR system.Can be in the Systems for optical inspection that PCR system includes
The double-colored detecting system in the channels 12-, for monitoring the real-time pcr fluorescence from the channels 12- microfluid PCR boxes.The system can
To include exciting light (for example, blue and amber LED light source), one or more bandpass filters, and one or more focusing
Lens.It will be collected into condenser lens from the fluorescence passage path of PCR reactors (e.g., including in microfluid box) transmitting
In, by filter, and reach on photodiode.For the channels every PCR, including in systems, for inquiring
Two colors dedicated, the fixed independent optical element of each.
In some embodiments, detection limit is the reaction that 20DNA copied/inputted PCR reaction mixtures, for basic value
Minimum signal be 1.15.The 2 color fluorescence system can be for, for example, FAM (or equivalent) and Cal Red (or it is of equal value
Object) it uses.The system, which can have, is collected in about 100ms to about 600ms with the maximum rate of every about 2 seconds data points
The ability of fluorescence data.When collecting data from the channels PCR, the LED in adjacent channel increases the signal in sample intake passage small
In about 1% (for example, 0.5%).The noise of detection can be less than about 1% peak signal.When use dark current-correction-fluorescence-
When slope measurement, the fluorescence changeability in the channel-with fluorescence standard (for example, component #14000009) to-channel can be right
In both FAM and Cal Red Cv be 30% within.There are 12 using fluorescence standard (component #14000009) for FAM
Average dark current-correction-fluorescence-slope of the optical component in channel can be at about 30mV to about 90mV/ (% blue leds power supply)
Between.There is the average dark of the optical component in 12 channels using standard fluorescence box (component #14000009) for Cal Red
Electric current-correction-fluorescence slope should be between about 75mV to about 300mV/ (the amber LED powers of %).Each channel is averaged
Exciting power can independently change about 5% to about 100% with software.In the light source that reader internal can not activated to influence
Fluorescence reading.In some embodiments, opening or closing the lamp in room does not influence optical readings.
In some embodiments, system may include the 2- color fluorescence detection device weights with 12 distance about 8mm
The optical component of multiple object.Optical detection component can be positioned at the top of microfluid box, and excitation and transmitting transport through microcosmic
The PCR windows of fluid box.The hole of optical component can be harmonized with PCR reactors within 200 microns about +/-.Contain LED and light
The optical electron plate of detector can concordantly be matched with optical component top, each photodetector is recessed into its respective optical
In the hole in channel.When microfluid box is installed in systems, the power delivering that optical component can be used for will be about 20 to about 30 pounds exists
On the zone of action of microfluid box, average pressure is at least about 1psi.
Optical component can be made of aluminum, and surface present on optical path length can be anodizing to black, example
Such as, so that autofluorescence and light scattering minimize.Orifice plate with 12 slits, each slit about 10mm long and 1mm wide, can
For, such as limit the size of excitation hot spot and reduce background fluorescence.The thickness of optical component can be about 1.135+/-
0.005 inch.The bottom surface of optical component can be plane in +/- 1 mil, to provide uniformly pressure on microfluid box
Power.During optical component manufactures and optical component is assembled in system, hole should keep cleaning, and without fragment.
In some embodiments, the system may include excitation optics, relative to the standard on PCR boxes surface, excitation
Path angle is equal to 55+/- 0.5 inches.One exemplary arrangement of the optical element in excitation path is in order LED, saturating
Mirror, filter, hole and PCR samples.System can use plano-convex excitation lens (for example, PCX, 6X9, MgF2TS), use plane
Side is against PCR sample orientations.It is included in optical device, one or more excitation paths with taper can be with this
Sample designs, so that lens and filter can be placed on inside hole, to provide the hot spot bigger than orifice plate.The position of LED and sample can
To be fixed, because the design may include fixed obtainable optical device thickness.Lens and filtering can be measured
The position of device is to provide excitation spot (excitation spot) size of about 6mm along the length in the channels PCR.Excite optics device
Part may include LED such as Luxeon components #LXK2-PB 14-NO 0 (for example, being excited for FAM) comprising about 470nm
The centre wavelength of (blue) has about 75 nanometers or less half-band width (for example, being excited for FAM).Excite optical device
Can also include LED, such as Luxeon components #LXK2-PL12-Q00 (for example, for Cai Red excitations) comprising 575nm
The centre wavelength of (amber), half-band width are about 75 nanometers or less (for example, for Cal Red excitations).Excite optical device
The middle LED used can remain stable for recycling for about 5 years or more or about 10,000 times.
The system may include transmitting optical device, and relative to the standard on PCR boxes surface, transmission path angle is equal to about
15+/- 0.5 inches.One exemplary arrangement of the optical element in transmission path, in order, be PCR samples, hole, filter,
Lens and photodetector.Diversing lens can be plano-convex (for example, PCX, 6 × 6MgF2TS), and plane side is against photodetector.
Transmitting optical device may include one or more holes for transmission path, has cone, can so design, so as to
The light of detection is set to maximize when filter and lens being made to place safely.Photodetector can be fixed relative to the position of sample
, because the design may include fixed obtainable optical component thickness.The position of lens and filter can be measured
To provide the transmitting spot size of 6mm along the length in the channels PCR.It can be used for emitting the exemplary photodetector of optical device
It is Hamamatsu silicon photodetectors, with lens, S2386-18L.
In some embodiments, system may include a diameter of about 6.0+/- 0.1mm, and thickness is about 6.0+/- 0.1mm
One or more filters, it is a diameter of to open hole less than or equal to about 4mm.Filter may include being placed on mounting ring
The melanism edge treated carried out before.If it does, the mounting ring can be metal and be anodizing to black.Filter can
To be manufactured from optical glass, surface quality is about 0 ° according to F/F per Mil-C-48497a, AOI, 1/2 cone AOI be about+
8 °, and can be that humidity and temperature are stablized within the recommended operating range of system.Exemplary filter can be from Omega
Optical Brattleboro, VT 05301 is obtained.
The system may include one or more FITC exciters filters (for example, PN 14000001), have
Omega part numbers 481AF30-RED-EXC (for example, figure #2006662), for example, being excited for FAM.These filters can have
There is the cutoff wavelength of the start wavelength and about 496+0/-4nm of about 466+/- 4nm.The transmission of the filter of the type can be more than
Or equal to about the 65% of peak value.These filters can have following retardance efficiency, for ultraviolet wavelength to about 439nm, greatly
In or be equal to OD4, for about 651nm to the wavelength of about 1000nm, more than or equal to OD4, for about 501nm to about 650nm's
Wavelength is greater than or equal to OD5, and for about 503nm to the wavelength of about 580nm, in theory, is greater than or equal to OD8.
The system may include one or more amber exciter filter (Amber Exciter Filter) (examples
Such as, PN 14000002), there is part number 582AF 25-RED-EXC (for example, figure #2006664), for example, being used for Cal RED
Excitation.These filters can be with the cutoff wavelength of the start wavelength and about 594+0/-5nm of about 569+/- 5nm.The type
The transmission of filter can be greater than or equal to about the 70% of peak value.In theory, for about 600nm to the wavelength of about 700nm, this
A little filters can have the retardance efficiency more than or equal to OD8.
The system may include one or more FITC transmitter filters (for example, PN 14000005), have component
Number 534AF 40-RED-EM (for example, figure #2006663), for example, emitting for FAM.These filters can have 514+/-
The start wavelength of 2nm and the cutoff wavelength of 554+/- 5nm.The transmission of the filter of the type can be greater than or equal to the pact of peak value
70%.These filters can have following retardance efficiency:For, to the wavelength of about 507nm, being greater than or equal to from ultraviolet light
OD5 in theory, is greater than or equal to OD8, and from about 593nm to about 765nm's from about 400nm to the wavelength of about 504nm
Wavelength is averagely greater than or equal to OD4.
The system may include one or more amber emission device filters (for example, PN 14000006), have portion
Piece number 627AF 30-RED-EM (for example, figure #2006665), for example, for Cal RED transmittings.These filters can have
The start wavelength of 612+5/-0nm and the cutoff wavelength of 642+/- 5nm.The transmission of the filter of the type can be greater than or equal to
About the 70% of peak value.These filters can have following retardance efficiency:For, to the wavelength of about 605nm, being more than from ultraviolet light
Or it is equal to OD5, from about 550nm to the wavelength of about 600nm, in theory, it is greater than or equal to OD8, and from about 667nm to about
900nm is averagely greater than or equal to OD5.
Embodiment 20:Exemplary 3- layers of box
Described herein is the exemplary specification for designing and assembling microfluid box, and is used about the box
In for example, the exemplary explanation of system as described herein.In some embodiments, the box can have and be copied equal to 20
The maximum detection limit (for example, 20/4 μ of copy) of shellfish/reaction volume, target is detected as 10 copies/reaction volume.The box can be
40 minutes or less time interior 45 reaction cycles of execution (for example, 45 cycles in 40 minutes, 45 cycles in 20 minutes, 15
45 cycles in minute, etc.).The box can utilize two color detections, for example, it uses FAM (or equivalent) and CAL
RED (or equivalent) fluorescent dye.The result that the box obtains and the knot for using standard real-time PCR instrument to obtain will be used
Fruit is compared.
In some embodiments, the box can be disposable, disposable box, can be according to general reality
Room step is tested to abandon.The box can be 4.375 inches long and 2.800 inches wide, and thickness is 0.094+/- 0.005 inches.Institute
It may include the feature for allowing the box and such as system as described herein interface to state box.Exemplary interface characteristics include PCR
The top of micro- base on conduit wall and the channels PCR is (the SPI A1/A2/A3) fully polished, can be easily in PCR
Reactor (for example, included in described box) transmits excitation and transmitting light between detecting system (for example, analyzer).The box
It may include hot interface, be located on the bottom of the box, be used for and analyzer interface.Hot interface can have thin laminate material
(for example, it is less than 150 microns of thickness, 100 microns of thickness, etc.) to promote heat to be transmitted to from heater wafer, for example, the PCR of the box
Channel.
The box may include with one or more mechanical interfaces of such as analyzer.For example, the box can be at one
Or there is recess on multiple angles, it can be matched with the respective shapes in the heater member of analyzer.The recess and corresponding
Shape the box can be made only to be placed in one way in the disk of such as system as described herein.In some embodiments
In, the box has single recess in one of the angle, and excess-three angle has the least radius of 1mm, described in promotion
Box is placed in analyzer.During use (for example, when being placed in system as described herein and executing such as PCR's
Function), the box can be squeezed, pressure against heater wafer (against opposite side positioning) on a side by optical component
It is about 1psi or bigger (for example, 0.99psi, 1.2psi, etc.).When in the disk for being located in analyzer, the box can have
+/- 200 microns of adjustment breaks bounds (alignment slop), so that user easily places and removed from analyzer disk
The box.The box can have there are two protrusion, be each 1mm wide, and fixed along two long sides of the box
Position, so that heating surface extends under the reference plane (datum) of the disk.
In some embodiments, the box can have following function specification.The box may include ingate, example
Such as, it is cone shape, the height apart from box top is 1mm.Cone can have at the top of the cone in 3mm
Diameter, and the diameter of the width of matching microchannel (for example, access road) can be tapered downwardly, inlet cone is by fluid
It is connected to the microchannel.Ingate can be fluidly connected to PCR reactors by access road, have for example, about 4.25 μ l extremely
The internal volume (for example, 4.22 μ l, 4.5 μ l, 4.75 μ l, etc.) of 4.75 μ l.Exporting microfluidic channels can be by PCR reactor
It is fluidly connected to overflow chamber.The box can also include outlet taps.
Input PCR samples (for example, reaction mixture) can be about 6.0 to 7.0 channels μ l/PCR (for example, 5.9 μ l/ are logical
Road, 6.4 channels μ l/, 7.1 channels μ l/, etc.), and can be introduced into the box by such as pipette by ingate.It can
Reaction mixture is transported to PCR reactors via access road, wherein reaction mixture can be detached (for example, by valve
Door seal is locked) to prevent reaction mixture evaporation or the movement during thermal cycle.Once the mixture is sealed in the interior
Portion, then analyzer can start the real-time PCR of multiplexing in some or all of reaction mixture (for example, 4.5 μ l, are equal to
The Fluid Volume of reative cell internal volume, etc.).
The microfluid base of the box may include one or more following specifications.The material of micro- base can be optics
Transparent (for example, the optical transmission with about 90% or bigger, 3mm is thick, meets ASTMD1003, etc.), there is autofluorescence,
It is less than by the fluorescence of 2mm thickness ZEONOR 1420R transmittings, and with about 1.53 refractive index (ASTM D542).Micro- base
Material can conform to the injection moulding feature needed for the Microfluidic networks of the box.The material preferably with whole PCR
Reagent is compatible, and can be subjected to being up to about 130 DEG C of temperature of about 5 minutes or more, without being bent or melting.The box can be with
Including benchmark, it can be identified, be located in one or more (preferably two)s at the angle of base by HandyLab manufacturing equipments.It is described
Box may include flow element (for example, microchannel, valve, end floss hole, reagent inlet hole, reative cell, etc.), to execute institute
Function (for example, PCR) institute for stating box is required.
The other feature of base material may include following one or more.The minimum clearance of about 1mm can design
To ensure to seal successfully (for example, arriving analyzer) between functional character, and it is allowed in period of assembly and is simplified to fix equipment.It is described
Box can include dog-bone under small fluid path end, for example, in order to increase mould life.The bottom on microtool surface can
With roughening (for example, by steam grinding stone, EDM, etc.).Base material can be adhered to by label.
In some embodiments, the band used in the box may include the one or more of following specification.Layer
Pressure material can easily be administered to the bottom of microfluid base.The material of laminated material is preferably pin-free.Material and viscous
Mixture is preferably compatible with PCR reactive chemistries.The laminated material and glue used should not autofluorescence.The material can be through
It was bonded, is bent without losing up to 5 minutes by up to 130 DEG C, melting, or generate overstress on the box.It is micro- being applied to
After base, bubble (for example, to 130 DEG C up to 5 minutes) should not be formed within the adhesive layer when heated.Laminated material should
Less than 5 mils (mills) thickness, for example, to realize that fast speed heat is transmitted.
Following features can be had by being included in the high temperature wax in the box.The wax should have about 90+/- 3 DEG C (for example,
87 DEG C, 90 DEG C, 93.1 DEG C, etc.) fusing point, bio-compatible is reacted with PCR, there is wetability with micro- base material, and is had
There are melt viscosity ranges, for example, viscosity is in 100 DEG C=20mm2/ s and hardness is in 25 DEG C=8dmm.The main mark of the box
There can be following features.It can have the suitable adhesiveness for micro- feature, and surround with the thickness of 2-4 mils
Valve seal includes the notch for one or more PCR windows, and helps to remove the connector of the box (without viscous from analyzer
Mixture).Main mark can also have wearability on top surface, and be printable.Main mark, which can have, to be used for
The adjustment pattern up and down of the label, valve hole is completely covered, for suitably operating the valve.
The box may include the bar shaped code labeling being administered at the top of box, can by bar code reader (e.g., including
Bar code reader in analyzer) it reads, while box being mounted in analyzer.Bar shaped code labeling may include ProductName
Claim, lot number, term of validity, bar code (2D) and can be printed with.In addition, or it is alternatively possible to using laser or ink-jet
Bar code is applied directly to main box and marked by type printer.
May include following one or more by the packaging that the box is included therein:Mark of parcels, carton, carton mark
Note and/or operational manual.The packaging can be printed with, or label is attachable, is placed in polybag, receives
Contracting/extension packaging bag etc., and can be stacked in the form of 24 one group.There is no the bag-in-container of decisive sealing that should be kept
Free from dust pollutes.
The box may include that one or more valves (for example, temperature controls, the valve containing wax) are used to start, and stop
Only, the flowing of the material and/or inside the control box.Wax included in valve can be no voids, the gas
Steep the diameter having more than one half width of valve passage.Valve passage can have air trap.Wax can not invade before activity
Enter into fluid path.The wax can be filled into the beginning of fluid path opening.
The box may include microchannel and hole, so as to the hole have can easily No leakage with 175 μ l liquid reliefs
The size and shape of pipe suction nozzle interface.In some embodiments, the pore size diameter is between about 200 μm and about 4000 μm.
It microchannel can be between about 50 μm and about 1500 μm wide, and between about 50 μm and 1000 μm of height.
The box may include for control valve that fluid flows in the box (for example, by microchannel, reactor
Room, etc.).Valve flange, step, and general geometry can be designed to promote required precision flow during wax loads
And/or it stagnates.Valve geometry can be designed to provide wax distributing equipment limitation (for example, 75nL volumes=/-
25%).In some embodiments, the air chamber that falls progressively on valve is funnel shaped to help wax to load, and remaining is several
What shape is reduced to the terminal position that wherein wax is stagnated from funnel bottom.The road that wherein valve will flow into and block during use
Diameter can be sufficiently narrow (for example, 150-200 microns wide and deep), and with sufficient length so as to moving valve during use
It is effectively sealed when door.Valve wax temperature can be about 90 DEG C.When a part for obstruction microchannel in use, valve can be close
Envelope is to prevent fluid evaporator during thermal cycle and/or fluid from PCR reactor physical migrations.
The box may include one or more PCR sector domains for executing PCR on sample.PCR sector domain is (for example, PCR
Reactor) in channel may be designed so that, so that the temperature of channel content is uniformly maintained in about 1 DEG C of annealing temperature.
Conduit wall can be with the polishing of SPIA1/A2/A3.
In some embodiments, the box is designed to arrive the temperature of about 86 °F (about 15 °C to about 30 DEG C) at about 59 °F
It spends and executes diagnostic test in the humidity range of range and about 15% relative humidity to about 80% relative humidity.Box is designed in room
Interior use is used in 2000m height below, and in non-condensing humidity (for example, the maximum of the temperature for being up to 31 DEG C is opposite
Humidity is 80%, is linearly reduced to 50% relative humidity at 40 DEG C) under the conditions of use when be safely effectively.
In use, the PCR product generated in the box may remain in used box, for example, so that cross contamination
Possibility minimize.The box may be designed so that, so that when it is packed, 4 feet of the box fall and will not destroy box.
The box is designed to after being exposed to following condition not execute destructively.For specified storage life, the box is answered
When being stored in 4 DEG C to 40 DEG C.Being exposed to the temperature between -20 DEG C and 4 DEG C or between 40 DEG C and 60 DEG C should occur to be no more than 24
Hour.The Typical gas pressures that the box can be resistant to gas conveying change.
The box can mark (for example, in order to differentiate the box, adapt to adjust, etc.) with following message.The label can
To contain the label " only for research ", if applicatory and ce mark, if applicatory.Label can contain company name
Claim and indicate (for example,), part number (for example, 55000009), component names (the non-rows of 12x Cartridge-
Put), lot number (for example, LOT 123456), term of validity (for example, 06/2015) writes space, according to bar code specification
Bar code (other place descriptions), and/or " 48108 USA of Handylab, Inc., Ann Arbor, MI ".
The box may include in carton, and the carton can contain information such as, part number (for example,
55000009), component names (the non-discharge of 12 × box -), quantity (for example, 24), lot number (for example, criticizing 123456), the term of validity
It limits (for example, 06/2015), optional UPC code, " being manufactured by HandyLab companies, 48108 U.S. Ann Arbor, MI ", statement
The carton label of storage limitation, ce mark (if applicatory) and/or AR titles and address.
Box packaging may include that paper bag is wrapped up in ensure that multiple boxes are filled with clean packaging to prevent from destroying together, example
Such as, carry out self-excited oscillation.Box cartons may include feature, and such as, for the accordance of ASTM6159, carton can store in office
Where upwards, it may not be necessary to the refrigeration of carton or frangible label, and other cold packaging can not needed.The storage longevity of box
Life is 12 months or more.
The box can meet IEC 61010 (NRTL tests), and FDA inventories can be needed for clinical distribution.
The box used in clinical laboratory apparatus can meet whole QC Quality System requirements.The box that research is only used in commercial apparatus can be with
Meet whole HandyLab QC Quality Systems requirements.The box (α or β tests) for being only used for research purposes, which can be design/manufacture, to be chased after
It traces back to DHR (manufacture record).
Foregoing description is intended to illustrate many aspects of the present invention.It is not intended to the examples provided herein limitation present invention's
Range.The technology fully described at present, it will be readily apparent to one of ordinary skill in the art that without departing substantially from appended claim
Spirit or scope in the case of, many changes and modifications can be carried out to it.
Claims (29)
1. a kind of microfluid base, the microfluid base include:
Multiple sample channels, wherein each in the multiple sample channel includes Microfluidic networks, the microfluid
Network has in a manner of being in fluid communication with each other:
Entrance;
First valve and the second valve;
Reative cell;
Floss hole;
Lead to the first passage of the reative cell from the entrance via first valve;With
Lead to the second channel of the floss hole from the reative cell via second valve;
Wherein described first valve and the second valve include temperature-responsive substance, and the temperature-responsive substance melts simultaneously when heated
And the sealing reative cell.
2. the microfluid base of claim 1, wherein each in the multiple sample channel is configured to independently of other
Channel expands one or more nucleic acid.
3. the microfluid base of claim 1, the microfluid base be configured to the reative cell it is at least one in
Carry out real-time PCR.
4. the microfluid base of claim 1, wherein each in the entrance is configured to pipette tip sealing simultaneously
And receive a certain amount of sample from pipette tip.
5. the microfluid base of claim 4, wherein the amount of the sample is 1-20 μ l.
6. the microfluid base of claim 4, wherein entrance include the reversing frusto-conical configuration of at least 1mm high, and
The diameter with 1-5mm at its widest point for receiving pipette tip entrance.
7. the microfluid base of claim 1, wherein the multiple sample channel entrance of each is to be located remotely from each other interval
, to allow from more head of pipette distributors while load.
8. the microfluid base of claim 1, wherein the reative cell has the volume of 1-20 μ l.
9. the microfluid base of claim 1, wherein the multiple sample channel is 12 channels.
10. the microfluid base of claim 1, the microfluid base further includes being located in above each reative cell
Fluoroscopic examination window.
11. a kind of microfluid box, the microfluid box includes the microfluid base of claim 1.
12. the microfluid box of claim 11, the microfluid box further includes recording element, and the recording element ensures institute
Box is stated with single-orientated to be received by complementary diagnostic device.
13. the microfluid box of claim 11, including reative cell, ingate and valve for the reative cell to be isolated
Each Microfluidic networks be limited in single base layer.
14. the microfluid box of claim 11, wherein the base is rigid base and is non-ooze for air or liquid
Permeability, and the box operate during air or liquid it is into or out substantially only can pass through the entrance or
Floss hole.
15. a method of it is independently expanded on multiple samples containing polynucleotides, the method includes:
The multiple sample is respectively introduced into microfluid box;
Detach the sample in the microfluid box;With
The polynucleotides in the multiple sample are expanded by continuous temperature cycles are applied independently to each sample.
16. the method for claim 15, wherein the box includes multiple reative cells.
17. the method for claim 16, wherein the reative cell is configured to that the multiple sample is allowed to carry out heat independently of each other
Cycle.
18. the method for claim 16, wherein it includes that separation is the multiple anti-to detach the sample in the microfluid box
Answer the sample in room.
19. the method for claim 18, wherein it includes by the multiple sample to detach the sample in the multiple reative cell
It moves independently of each other into each of multiple reative cells.
20. the method for claim 19, wherein the sample detached in the multiple reative cell further includes:
The multiple sample is moved independently of each other into each of the multiple reative cell;
Detect presence of the multiple sample in the reative cell;With
The valve on the reative cell downstream side is closed, and closes the valve on the reative cell upstream side.
21. the method for claim 20, wherein detecting presence of the multiple sample in the reative cell and including and reative cell
Place LED and photodiode to optical communication.
22. the method for claim 15, wherein expand the polynucleotides in the multiple sample include independently activation with it is each
One or more heaters of sample independence thermal communication.
23. the method for claim 15, wherein the multiple sample be respectively introduced into microfluid box including:
Multiple pipettes comprising the sample are placed in multiple entrances of the microfluid box;With
The sample is independently assigned to from the multiple pipette in each in the multiple entrance.
24. the method for claim 15, wherein the multiple sample is introduced into the microfluid box simultaneously.
25. the method for claim 15, wherein the multiple sample is successively introduced in microfluid sample.
26. the method for claim 15, the method further includes polynucleotides the depositing in the multiple sample of detection amplification
.
27. the method for claim 26, wherein the presence for detecting the polynucleotides of amplification includes detecting the multinuclear from being expanded
The fluorescence signal of thuja acid.
28. the method for claim 27, wherein it includes that will scan reading to detect the fluorescence signal from the polynucleotides expanded
For head by the microfluid box, the scanning read head includes multiple detectors with LED and photodiode.
29. a method of it is independently expanded on multiple samples containing polynucleotides, the method includes:
The multiple sample is introduced into microfluid box, wherein the box have multiple reative cells, the reative cell by with
Being set to allows the multiple sample to carry out thermal cycle independently of each other;
The multiple sample is moved independently of each other into each of the multiple reative cell;
Detach the sample in the multiple reative cell;With
Multinuclear included in the multiple sample is expanded by continuous temperature cycles are applied independently to the reative cell
Thuja acid.
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US11/985,577 US7998708B2 (en) | 2006-03-24 | 2007-11-14 | Microfluidic system for amplifying and detecting polynucleotides in parallel |
CN2008801067603A CN101802164B (en) | 2007-07-13 | 2008-07-14 | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
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CN2008801067603A Division CN101802164B (en) | 2007-07-13 | 2008-07-14 | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
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CN108405002B CN108405002B (en) | 2020-09-22 |
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CN202010903405.1A Pending CN112094739A (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
CN201310456052.5A Active CN103695307B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological sample |
CN201810120041.2A Active CN108405002B (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
CN201310455953.2A Active CN103756867B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological samples |
CN201310455954.7A Active CN103725592B (en) | 2007-07-13 | 2008-07-14 | Integrated device for nucleic acid extraction and diagnostic test on multiple biological samples |
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CN201310456193.7A Active CN103740588B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological samples |
CN201310455322.0A Active CN103695310B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological samples |
CN201810170491.2A Active CN108165462B (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
CN201310455967.4A Active CN103725603B (en) | 2007-07-13 | 2008-07-14 | Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples |
CN201510994207.XA Active CN105441312B (en) | 2007-07-13 | 2008-07-14 | Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples |
CN201310459896.5A Active CN103695292B (en) | 2007-07-13 | 2008-07-14 | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
CN201310456179.7A Active CN103695291B (en) | 2007-07-13 | 2008-07-14 | Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples |
CN201710406173.7A Active CN107233943B (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
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CN202010903405.1A Pending CN112094739A (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
CN201310456052.5A Active CN103695307B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological sample |
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CN201310455954.7A Active CN103725592B (en) | 2007-07-13 | 2008-07-14 | Integrated device for nucleic acid extraction and diagnostic test on multiple biological samples |
CN2008801067603A Active CN101802164B (en) | 2007-07-13 | 2008-07-14 | Integrated apparatus for performing nucleic acid extraction and diagnostic testing on multiple biological samples |
CN201310456193.7A Active CN103740588B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological samples |
CN201310455322.0A Active CN103695310B (en) | 2007-07-13 | 2008-07-14 | For carrying out the integrating device of nucleic acid extraction and diagnostic test on multiple biological samples |
CN201810170491.2A Active CN108165462B (en) | 2007-07-13 | 2008-07-14 | Integrated device for performing nucleic acid extraction and diagnostic tests on multiple biological samples |
CN201310455967.4A Active CN103725603B (en) | 2007-07-13 | 2008-07-14 | Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples |
CN201510994207.XA Active CN105441312B (en) | 2007-07-13 | 2008-07-14 | Integrating device for carrying out nucleic acid extraction and diagnostic test on multiple biological samples |
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